WAVE1在上皮性卵巢癌恶性行为中的作用及其机制的初步研究
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摘要
卵巢恶性肿瘤、子宫颈癌和子宫内膜癌是女性生殖器最常见的三大恶性肿瘤。卵巢恶性上皮性肿瘤占卵巢恶性肿瘤的85~90%。上皮性卵巢癌（Epithelial ovarian cancer，EOC）在女性生殖道恶性肿瘤中死亡率最高，全世界每年有近204，000女性诊断患有卵巢癌，近125，000死于该疾病，对妇女生命造成严重威胁。卵巢癌起病隐匿、原发灶隐蔽，患者早期缺少临床症状、不易发现，3/4的患者初诊时通常已经进展到疾病中晚期（FIGO III～IV期），且肿瘤具有易播散转移、术后易复发且易产生化疗耐药等特点。随着医学和科技水平的进步，即使采取了包括临床肿瘤细胞减灭术和联合化疗等综合治疗手段，并改进了外科手术方法、增加了新的化疗方案，对于最常见的EOC，长期以来，国内、外的资料显示该疾病患者5年生存率始终停留在30％左右。卵巢癌的侵袭转移恶性行为是导致卵巢癌治疗失败，死亡的主要原因，因此它的恶性生物学行为及其分子生物学机制一直是肿瘤学研究领域中的热点。
恶性肿瘤的发生、发展及转移是一个复杂的生物学过程，癌细胞先在原位生长，而后向邻近组织侵袭，使其发生破坏，然后从原发灶脱离，侵入血道﹑淋巴道，进而在远处形成转移瘤。在这一过程中，癌细胞向邻近组织的侵袭生长是肿瘤转移发生的起始步骤，而这种对邻近组织的侵袭性又依赖于癌细胞的定向极化运动能力，即癌细胞伪足往某一方向持续延伸的动力，这一动力是通过肌动蛋白的聚合所提供。因此探讨癌细胞极化运动机制，进而控制肌动蛋白在癌细胞伪足部位的聚合，可以达到早期控制癌细胞侵袭转移的目的。课题组前期研究采用反向捕获抗体芯片技术在对“吸烟与粘液性卵巢癌的发病相关性研究”和在“上皮性卵巢癌早期诊断研究”中发现，Wiskott-Aldrich综合征蛋白家族富含脯氨酸同源蛋白1（Wiskott–Aldrich syndromeprotein family verprolin-homologous protein1，WAVE1）是同时存在于两组研究结果中血清抗体的差异性表达蛋白，可能是EOC细胞的一个标志蛋白。WAVE1基因在1998年发现并命名，主要负责将细胞信号从酪氨酸激酶受体和Rac传递至细胞骨架，从而发挥其调节肌动蛋白聚合及细胞骨架重排的作用并最终形成片状伪足。研究发现在黑色素瘤、前列腺癌、白血病等恶性肿瘤中，WAVE1均高度表达，提示WAVE1在肿瘤的侵袭转移过程中发挥着重要作用。但国内外目前尚无WAVE1在EOC恶性行为中的相关研究报道。因此，本课题将分为以下四部分对WAVE1在EOC恶性行为中的作用及其机制进行初步研究。
第一部分
WAVE1在上皮性卵巢癌中的表达及临床意义
目的：检测WAVE1在EOC组织标本中的蛋白表达情况，探讨EOC组织中WAVE1的表达与临床病理特征之间的相关性。
方法：
（1）采用免疫组织化学法检测223例EOC组织标本，29例交界性卵巢肿瘤标本，44例良性肿瘤标本和24例正常卵巢组织标本中WAVE1的表达情况，分析WAVE1的异常表达与临床病理特征之间的关系。
（2）采用Western blot法检测其中44例EOC组织标本，16例交界性卵巢肿瘤标本，32例良性肿瘤标本和22例正常卵巢组织标本中WAVE1的表达情况，并分析WAVE1的异常表达与临床病理特征之间的关系。
（3）采用Kaplan–Meier生存分析比较EOC患者组织中WAVE1表达强弱对生存时间的影响；Cox回归分析探讨有关EOC患者生存时间的影响因素。
（4）应用Western blot法检测EOC细胞株SKOV3，OVCAR-3，ES-2和3AO细胞中WAVE1蛋白表达情况，采用激光共聚焦显微镜分析WAVE1在卵巢癌细胞株中的亚细胞定位。
结果：
（1）免疫组织化学结果显示，在223例EOC组织中，163例（73.1%）呈WAVE1强阳性表达，60例（26.9%）呈WAVE1低表达或不表达；在交界性卵巢肿瘤、良性卵巢肿瘤和正常卵巢组织中分别有23例（79.3%）、37例（84.1%）、23例（95.8%）呈WAVE1不表达，差异均有统计学意义（P<0.05）。在EOC组织中，WAVE1蛋白的表达水平在FIGO III~IV期组织中显著高于I~II期（P<0.001），中低分化细胞中的表达显著高于高分化（P<0.001），血浆Ca-125≥35U/ml的EOC患者组织中表达显著高于Ca-125<35U/ml的患者组织（P=0.013），术后残余瘤≥1cm的EOC患者组织中表达显著高于术后残余瘤<1cm的患者组织（P=0.036），但与EOC患者年龄、病理类型、肿瘤大小、腹水及病灶单双侧无关（P>0.05）。
（2）Western blot结果显示，WAVE1在EOC组织中的表达（0.930±0.188）显著高于交界性卵巢肿瘤（0.586±0.098）、良性卵巢肿瘤（0.542±0.103）和正常卵巢组织（0.441±0.097），差异均有统计学意义（P<0.05）。在EOC组织中，WAVE1蛋白的表达水平与EOC FIGO分期、组织分化、血浆Ca-125及术后残余瘤有关（P<0.05），而与患者年龄、病理分型、肿瘤大小、腹水、病灶单双侧无关（P>0.05），该实验结果与免疫组织化学结果一致。
（3）生存分析显示WAVE1低表达的EOC患者生存时间显著长于WAVE1高表达患者（P<0.05），多变量分析表明WAVE1高表达、EOC分期中晚期和不理想的肿瘤减灭术分别是EOC预后的独立因素。
（4）WAVE1在EOC细胞株SKOV3，3AO，OVCAR-3和ES-2细胞中均为高表达（分别为1.218±0.112，1.111±0.084，1.057±0.148，和0.968±0.055）；激光共聚焦显微镜观察到WAVE1与肌动蛋白均共表达于卵巢癌细胞的细胞质和细胞膜上。
结论：WAVE1在EOC组织和细胞中均呈现高表达。高水平WAVE1
与EOC分期、肿瘤分化、血浆Ca-125值和术后残余瘤有关。WAVE1的高表达与EOC侵袭和不良预后有关，提示WAVE1可能在EOC恶性
行为中发挥重要作用。
第二部分WAVE1基因特异性shRNA慢病毒载体的构建及稳定转染上皮性卵巢癌细胞株的筛选
目的：应用RNA干扰（RNA interference，RNAi）技术设计构建WAVE1的短发夹状RNA（short hairpin RNA，shRNA）慢病毒载体，构建筛选稳定转染卵巢癌细胞株，为后续研究奠定基础。
方法：
（1）设计并化学合成两对含高效的靶向WAVE1基因的重组质粒和阴性对照。通过双酶切实验和DNA测序法对重组质粒进行鉴定。
（2）将经测序验证正确的重组质粒及慢病毒包装质粒，通过Lipofectamine TM2000共转染到293T细胞后收集、提纯、测定滴度。采用慢病毒载体转染法转染至SKOV3细胞中，并建立稳定转染细胞株。
（3）采用Western blot法和Real time PCR法分别检测未转染组、阴性对照组及转染组细胞中WAVE1蛋白和mRNA表达量的变化，验证和筛选WAVE1基因抑制效应显著的稳定转染细胞株。
结果：
（1）成功设计并合成两条WAVE1特异性shRNA，双酶切实验和
DNA测序报告显示，基因重组技术成功构建WAVE1基因RNA干扰慢
病毒载体，测定滴度为2.2×108U/ml。
（2）慢病毒载体介导的WAVE1-shRNA1、WAVE1-shRNA2和阴性对照成功转染SKOV3细胞，采用嘌呤霉素成功筛选获得稳定表达的单克隆细胞株。
（3）通过Western blot法与Real time PCR法检测、验证和筛选，获得WAVE1基因抑制效果显著的稳定转染EOC细胞株SKOV3-Ri1细胞。
结论：成功靶向构建了WAVE1基因的特异性重组质粒。利用慢病毒载体成功筛选获得了WAVE1基因抑制效果显著的卵巢癌稳定转染细胞株，为进一步研究WAVE1恶性生物学行为及其分子机制奠定实验基础。
第三部分
慢病毒介导的WAVE1基因沉默对上皮性卵巢癌细胞恶性行为的影响
目的：探讨WAVE1基因沉默后对SKOV3细胞生长、增殖、粘附和侵袭等恶性生物学行为的影响。
方法：
（1）采用激光共聚焦显微镜观察WAVE1基因沉默前后SKOV3细胞的形态学改变。
（2）Transwell小室检测WAVE1基因沉默前后SKOV3细胞的迁移、侵袭能力变化。
（3）细胞粘附实验分析WAVE1基因沉默前后SKOV3细胞的粘附功能改变。
（4）MTT比色法测定WAVE1基因沉默前后SKOV3细胞的增殖能力改变。
（5）软琼脂克隆形成实验观察WAVE1基因沉默前后SKOV3细胞的群体依赖性和增殖能力变化。
（6）裸鼠皮下移植瘤实验观察WAVE1基因沉默前后SKOV3细胞的成瘤能力变化。
结果：
（1）干扰WAVE1表达能够使EOC细胞形态发生变化：激光共聚焦显微镜观察到，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞呈现去极化，丝状伪足、片状伪足形成能力显著减弱，形态变圆。
（2）干扰WAVE1表达能够抑制EOC细胞侵袭转移能力：Transwell小室迁移实验结果显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞穿过聚碳酸脂膜的迁移细胞数显著减少（P<0.05）。
Transwell小室侵袭实验结果显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞穿过Matrigel的侵袭细胞数显著减少（P<0.05）。
细胞粘附实验显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞的粘附能力显著降低（P<0.05）。
（3）干扰WAVE1表达能够抑制EOC细胞生长增殖的恶性程度：
MTT法检测EOC细胞的增殖结果显示，与阴性对照组和正常对照组相比，在转染后1d、2d、3d、4d和5d，干扰组SKOV3-Ri1细胞生长曲线较平缓，细胞生长速度明显减缓（P<0.05）。
软琼脂克隆形成实验显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞细胞生长速度变慢，克隆形成数目显著减少（P<0.05）。
（4）干扰WAVE1表达能够抑制裸鼠皮下成瘤的恶性行为能力：
与阴性对照组相比，干扰组移植瘤成瘤能力显著减弱，瘤体生长速度缓慢，体积减小。
结论：WAVE1基因沉默后改变了卵巢癌细胞SKOV3的形态变化，显著抑制了SKOV3细胞的增殖能力和侵袭转移能力，反向证实了WAVE1在EOC增殖和侵袭转移恶性行为中的作用，具有作为EOC预防、治疗基因靶点的潜在价值。
第四部分WAVE1参与上皮性卵巢癌恶性行为的分子机制研究
目的：探讨WAVE1参与上皮性卵巢癌增殖和侵袭转移恶性行为的可能分子机制。
方法：
（1）采用HE染色观察裸鼠移植瘤组织形态学变化。
（2）采用免疫组织化学法和Western blot法检测干扰组与阴性对照组移植瘤组织中与增殖、侵袭转移相关蛋白cyclin D1、VEGF、MMP-2、MMP-9和E-cadherin的水平变化。
（3）采用Western blot法检测WAVE1基因沉默前后卵巢癌细胞中与增殖、侵袭转移相关信号转导通路蛋白AKT与p-AKT，p38MAPK与p-p38MAPK，ERK1/2与p-ERK1/2蛋白表达水平变化。
结果：
（1）HE染色后可见，SKOV3-NC组肿瘤细胞失去极性，排列不规则，而SKOV3-Ri1组细胞可见极性，排列相对整齐。
（2）免疫组织化学及Western blot结果均显示，与SKOV3-NC相比，SKOV3-Ri1移植瘤组织中cyclin D1、VEGF、MMP-2、MMP-9表达水平显著降低，而E-cadherin表达水平上升（P<0.05）。
（3）Western blot法检测信号转导通路相关的蛋白结果显示，SKOV3-Ri1细胞中AKT蛋白、p-AKT蛋白及p-p38MAPK蛋白显著低于阴性对照组SKOV3-NC细胞（P<0.05）。而两组中ERK1/2蛋白、p-ERK1/2蛋白及p38MAPK蛋白无明显改变（P>0.05）。
结论：在EOC细胞中，上调的WAVE1可能通过激活PI3K/AKT和p38MAPK信号转导通路，介导其下游肿瘤相关基因参与EOC的恶性行为。WAVE1有可能是PI3K/AKT和p38MAPK信号转导通路潜在的调节因子。
The ovarian malignant cancer, cervical cancer and endometrialcarcinoma are the most commongynecological malignancies.85-90%ofovarian malignant cancer is epithelial ovarian cancer (EOC). EOC is acommongynecological malignancy that is associated with an unfavorableoutcome, and it is the fifth-leading cause of death in females. Worldwide,nearly204,000women are diagnosed, and125,000die due to ovariancancer each year. Seventy-five percent of EOC patients are diagnosed at anadvanced and metastatic stage because of the lack of sensitive screeningtests or early symptoms. To date, the cellular/molecular mechanisms ofEOC metastasis remain poorly understood, even though extensive clinicaland basic research effortshave been undertaken. Identification of novelmolecular markers and the cellular/molecular mechanisms of EOC couldimprove the prediction of metastasis, novel therapeutic methods and furtherunderstanding of EOC progression.
The initial and essential step of cancer cell metastasis is cell migration.Invasive cancer cells must use their remodeled actin cytoskeleton tomigrate through the extracellular matrix (ECM) and enter the blood or lymphatic system. Reorganization of actin filaments is tightly regulated bya variety of proteins which are essential for cell movement. Our previouslystudy using the innovative reverse capture antibody microarray to identifyautoantibody biomarkers in the plasma samples of EOC patients suggesteda significantly elevated expression of Wiskott–Aldrich syndrome proteinfamily verprolin-homologous protein1(WAVE1) in EOC plasma comparedwithhealthy controls. WAVE1, which belongs to Wiskott–Aldrichsyndrome protein (WASP) family protein,has been proposed as acting as anenhancer. Various researchhas found that WAVE1is critical for cancer cellmigration, invasion and metastasis. Down-regμlation of WAVE1has beenfound to be related to decreased invasion of prostate cancer cells, andresμlts sμggest that it might be used as a molecμlar target for preventingcell metastasis. WAVE1protein was overexpressed in malignant melanomacells, which showedhigher Rac activity than non-invasive andnon-metastatic cells. A recent studyhas shown that WAVE1is a novelregulator of apoptosis that is involved in the multidrug resistance ofleukemia cells.however, no studyhas assessed the expression of WAVE1inpatients with EOC or investigated the role of WAVE1in ovarian cancer cellinvasion and metastasis. In the present study, we aimed to examine thefunction and mechanism of WAVE1in malignant behaviors in EOC by thefollowing four parts.
PART ONETHE EXPRESSION AND CLINICAL SIGNIFICATION OF
WAVE1IN EPITHELIAL OVARIAN CANCER
Objectives: This study aims to determine the effect of WAVE1expression and investigate a possible relationship between WAVE1andprognosis in EOC.
Methods:
1. WAVE1protein level was measured in223EOC specimens byimmunohistochemical staining, and the association of WAVE1proteinexpression with clinicopathological characteristics in223cases of invasiveovarian carcinomas was investigated.
2. WAVE1protein level was measured in46EOC specimens byWestern blot, and the association of WAVE1protein expression withclinicopathological characteristics in46cases of invasive ovariancarcinomas was investigated.
3. Survival analysis was performed to assess the correlation betweenWAVE1expression and survival.
4. Expression of WAVE1in ovarian cancer cell lines was evaluated byWestern blot analysis and immunofluorescence.
Results:
1.Immunohistochemical staining showed that WAVE1was over- expressed in EOC compared with samples from a non-invasive ovariantumor and normal ovaries (P<0.05). The expression of WAVE1wassignificantly associated with advanced FIGO stage, poorgrade, serumCa-125and residual tumor size (P<0.05).
2.Western blot analysis showed that WAVE1was overexpressed inEOC compared with samples from a non-invasive ovarian tumor andnormal ovaries (0.930±0.188,0.586±0.098,0.542±0.103, and0.441±0.097,respectively)(P<0.05). The expression of WAVE1was significantlyassociated with advanced FIGO stage, poorgrade, serum Ca-125andresidual tumor size (P<0.05).
3.Survival analysis showed that patients with low WAVE1staininghada significantly better survival compared to patients withhigh WAVE1staining (P<0.05). In multivariate analysis, WAVE1overexpression,advanced stage and suboptimal surgical debulking were independentprognostic factors of poor survival.
4.By Western blot analysis, WAVE1expression was detected in fourovarian cancer cell lines (1.218±0.112,1.111±0.084,1.057±0.148, and0.968±0.055, respectively). Immunofluorescence was performed todemonstrate WAVE1expression in SKOV3and3AO cell lines.
Conclusions: Our present study finds that WAVE1overexpression isassociated with an unfavorable prognosis. WAVE1is an independentprognostic factor for EOC, which suggests that it is a novel and crucial
predictor for EOC metastasis.
PART TWOCONSTRUCTION OF SHRNA LENTIVIRAL VECTORTARGETING WAVE1GENE AND SELECTION A STABLYTRANSFECTED EPITHELIAL OVARIAN CANCER CELLLINE
Objectives: This study aims to construct short hairpin RNA (shRNA)lentiviral vector targeting WAVE1gene and select a stably transfectedepithelial ovarian cancer cell line for the following studies.
Methods:
1.Designed and synthesized two WAVE1specific shRNA sequencesand one negative control sequence. Double restriction digestion and DNAsequencing were used to identified the recombinant plasmid.
2.The correct recombinant plasmid and lentiviral vector wereco-transfected into293T cells by Lipofectamine TM2000to collect andpurify lentivirus virus particles. Establishing stably transfected epithelialovarian cancer cell lines by the manufacturer’s protocol.
3.Identified the best inhibited effect of WAVE1in the stablytransfected epithelial ovarian cancer cell lines by western blot and real time PCR
Results:
1.The double restriction digestion and DNA sequencing showed wesuccessfully designed and synthesized two WAVE1specific shRNAsequences, with a titer of2.2×108U/ml.
2.According to the manufacturer’s protocol, we established stablytransfected ovarian cancer cell lines by puromycin.
3.The western blot and Real time PCR showed the protein and mRNAlevels of WAVE1were down-regulated in stably transfected ovarian cancercell lines. The SKOV3-Ri1cell line was with the more inhibited effect ofWAVE1.
Conclusions: Our present study successfully designed andsynthesized two WAVE1specific shRNA sequences. By lentivirus vector,weharvested the stably transfected epithelial ovarian cancer cell lineSKOV3-Ri1with the more inhibited effect of WAVE1.
PART THREEWAVE1GENE SILENCING VIA RNA INTERFERENCEIMPACT ON THE MALIGNANT BEHAVIOR OFEPITHELIAL OVARIAN CANCER CELLS
Objectives: This study aims to investigate the effect of WAVE1genesilencing via RNA interference impact on the proliferation, migration,invasion, and adhesion in SKOV3cells.
Methods:
1.The morphplogic changes of SKOV3cells before and afterinhibition of WAVE1were detected by confocal immunofluorescencemicroscopy.
2.The cell migration and invasion of SKOV3cells before and afterinhibition of WAVE1were analyzed by transwell assay.
3.The cell adhesion of SKOV3cells before and after inhibition ofWAVE1was tested by cell adhesion assay.
4.The cell proliferation of SKOV3cells before and after inhibition ofWAVE1was investigated by MTT assay.
5.The cell anchorage-independentgrowth of SKOV3cells before andafter inhibition of WAVE1was examined by soft agar assay.
6.The tumor formation of SKOV3cells before and after inhibition ofWAVE1was measured in nude mice.
Results:
1.WAVE1silencing induces morphologic changes:
The morphology of the SKOV3-Ri1, SKOV3-NC and SKOV3were examined using actin staining. The SKOV3-Ri1was unpolarized, missingtheir pseudopodia, presented reduced cellular protrusions, and wasreshaped compared with control cells.
2.WAVE1silencing decreases cell migration and invasion:
Transwell assays were carried out to determine the effects of WAVE1silencing on ovarian cancer cell migration and invasion. In SKOV3-Ri1, asignificant reduction in the number of migratory cells was observedcompared with the control cells (P<0.05), and there was also a significantdecrease in the number of invading cells compared with the control cells.
The SKOV3-Ri1presented a significant decrease in cell adhesioncompared with the control cells (P<0.05).
3.WAVE1silencing inhibits colony formation and cell proliferation:
Using the MTT assay, we found that SKOV3-Ri1presented asignificantgrowth-inhibiting effect on day2(P<0.05).
Using a soft agar assay, we found that the average number of coloniesformed by SKOV3-Ri1was significantly lower than the number formed bycontrol cells, and the size of the colonies was reduced (P<0.05).
4.WAVE1silencing inhibits tumor formation in xenografts in nudemice
We found that not only thegrowth rate but also the size of thexenografts of SKOV3-Ri1were significantly slower and smaller,respectively, compared with control cells.
Conclusions: Our present study showed the down-regulation ofWAVE1had a significant effect on cell morphological changes. WAVE1silencing decreased cell migration, cell invasion, cell adhesion, colonyformation and cell proliferation in vitro. In addition, we also found thatdown-regulation of WAVE1inhibited tumor malignant behaviors in vivo.
PART FOURTHE UNDERLYING MECHANISMS OF WAVE1REGULATING THE MALIGNANT BEHAVIOR OFEPITHELIAL OVARIAN CANCER
Objectives: This study aims to investigate the underlying mechanismsof WAVE1regulating proliferative and invasive malignant behaviors ofepithelial ovarian cancer.
Methods:
1.HE staining was used to analyze the morphological changes ofxenografts which formed by SKOV3-Ri1and SKOV3-NC.
2.Immunohistochemical staining and western blot analysis were usedto detect the levels of cyclin D1, VEGF, MMP-2, MMP-9, and E-cadherinin xenografts which formed by SKOV3-Ri1and SKOV3-NC.
3.Western blot analysis were used to examine proliferation-related signaling pathways that regulate cancer cell tumorigenesis and metastasis.The protein level of AKT, p-AKT, p38MAPK, p-p38MAPK, ERK1/2, andp-ERK1/2were tested in SKOV3-Ri1cells and SKOV3-NC.
Results:
1.HE staining showed the morphology of SKOV3-Ri1changed.
2.Immunohistochemical staining and western blot analysis showed thedown-regulation of WAVE1, MMP-2, MMP-9, VEGF, and cyclin D1expression, and the up-regulation of E-cadherin expression, were observedin xenografts formed by SKOV3-Ri1, compared with controls.
3.Western blot analysis indicated that total AKT, phospho-AKT, andphospho-p38protein levels were down-regulated in SKOV3-Ri1. Incontrast, no WAVE1silencing-induced changes were observed in totalERK1/2, phospho-ERK1/2, and p38levels.
Conclusions: Our present study showed WAVE1regulated themalignant behavior of epithelial ovarian cancer might through theactivation of the PI3K/AKT and p38MAPK signaling pathways.
恶性肿瘤的发生、发展及转移是一个复杂的生物学过程，癌细胞先在原位生长，而后向邻近组织侵袭，使其发生破坏，然后从原发灶脱离，侵入血道﹑淋巴道，进而在远处形成转移瘤。在这一过程中，癌细胞向邻近组织的侵袭生长是肿瘤转移发生的起始步骤，而这种对邻近组织的侵袭性又依赖于癌细胞的定向极化运动能力，即癌细胞伪足往某一方向持续延伸的动力，这一动力是通过肌动蛋白的聚合所提供。因此探讨癌细胞极化运动机制，进而控制肌动蛋白在癌细胞伪足部位的聚合，可以达到早期控制癌细胞侵袭转移的目的。课题组前期研究采用反向捕获抗体芯片技术在对“吸烟与粘液性卵巢癌的发病相关性研究”和在“上皮性卵巢癌早期诊断研究”中发现，Wiskott-Aldrich综合征蛋白家族富含脯氨酸同源蛋白1（Wiskott–Aldrich syndromeprotein family verprolin-homologous protein1，WAVE1）是同时存在于两组研究结果中血清抗体的差异性表达蛋白，可能是EOC细胞的一个标志蛋白。WAVE1基因在1998年发现并命名，主要负责将细胞信号从酪氨酸激酶受体和Rac传递至细胞骨架，从而发挥其调节肌动蛋白聚合及细胞骨架重排的作用并最终形成片状伪足。研究发现在黑色素瘤、前列腺癌、白血病等恶性肿瘤中，WAVE1均高度表达，提示WAVE1在肿瘤的侵袭转移过程中发挥着重要作用。但国内外目前尚无WAVE1在EOC恶性行为中的相关研究报道。因此，本课题将分为以下四部分对WAVE1在EOC恶性行为中的作用及其机制进行初步研究。
第一部分
WAVE1在上皮性卵巢癌中的表达及临床意义
目的：检测WAVE1在EOC组织标本中的蛋白表达情况，探讨EOC组织中WAVE1的表达与临床病理特征之间的相关性。
方法：
（1）采用免疫组织化学法检测223例EOC组织标本，29例交界性卵巢肿瘤标本，44例良性肿瘤标本和24例正常卵巢组织标本中WAVE1的表达情况，分析WAVE1的异常表达与临床病理特征之间的关系。
（2）采用Western blot法检测其中44例EOC组织标本，16例交界性卵巢肿瘤标本，32例良性肿瘤标本和22例正常卵巢组织标本中WAVE1的表达情况，并分析WAVE1的异常表达与临床病理特征之间的关系。
（3）采用Kaplan–Meier生存分析比较EOC患者组织中WAVE1表达强弱对生存时间的影响；Cox回归分析探讨有关EOC患者生存时间的影响因素。
（4）应用Western blot法检测EOC细胞株SKOV3，OVCAR-3，ES-2和3AO细胞中WAVE1蛋白表达情况，采用激光共聚焦显微镜分析WAVE1在卵巢癌细胞株中的亚细胞定位。
结果：
（1）免疫组织化学结果显示，在223例EOC组织中，163例（73.1%）呈WAVE1强阳性表达，60例（26.9%）呈WAVE1低表达或不表达；在交界性卵巢肿瘤、良性卵巢肿瘤和正常卵巢组织中分别有23例（79.3%）、37例（84.1%）、23例（95.8%）呈WAVE1不表达，差异均有统计学意义（P<0.05）。在EOC组织中，WAVE1蛋白的表达水平在FIGO III~IV期组织中显著高于I~II期（P<0.001），中低分化细胞中的表达显著高于高分化（P<0.001），血浆Ca-125≥35U/ml的EOC患者组织中表达显著高于Ca-125<35U/ml的患者组织（P=0.013），术后残余瘤≥1cm的EOC患者组织中表达显著高于术后残余瘤<1cm的患者组织（P=0.036），但与EOC患者年龄、病理类型、肿瘤大小、腹水及病灶单双侧无关（P>0.05）。
（2）Western blot结果显示，WAVE1在EOC组织中的表达（0.930±0.188）显著高于交界性卵巢肿瘤（0.586±0.098）、良性卵巢肿瘤（0.542±0.103）和正常卵巢组织（0.441±0.097），差异均有统计学意义（P<0.05）。在EOC组织中，WAVE1蛋白的表达水平与EOC FIGO分期、组织分化、血浆Ca-125及术后残余瘤有关（P<0.05），而与患者年龄、病理分型、肿瘤大小、腹水、病灶单双侧无关（P>0.05），该实验结果与免疫组织化学结果一致。
（3）生存分析显示WAVE1低表达的EOC患者生存时间显著长于WAVE1高表达患者（P<0.05），多变量分析表明WAVE1高表达、EOC分期中晚期和不理想的肿瘤减灭术分别是EOC预后的独立因素。
（4）WAVE1在EOC细胞株SKOV3，3AO，OVCAR-3和ES-2细胞中均为高表达（分别为1.218±0.112，1.111±0.084，1.057±0.148，和0.968±0.055）；激光共聚焦显微镜观察到WAVE1与肌动蛋白均共表达于卵巢癌细胞的细胞质和细胞膜上。
结论：WAVE1在EOC组织和细胞中均呈现高表达。高水平WAVE1
与EOC分期、肿瘤分化、血浆Ca-125值和术后残余瘤有关。WAVE1的高表达与EOC侵袭和不良预后有关，提示WAVE1可能在EOC恶性
行为中发挥重要作用。
第二部分WAVE1基因特异性shRNA慢病毒载体的构建及稳定转染上皮性卵巢癌细胞株的筛选
目的：应用RNA干扰（RNA interference，RNAi）技术设计构建WAVE1的短发夹状RNA（short hairpin RNA，shRNA）慢病毒载体，构建筛选稳定转染卵巢癌细胞株，为后续研究奠定基础。
方法：
（1）设计并化学合成两对含高效的靶向WAVE1基因的重组质粒和阴性对照。通过双酶切实验和DNA测序法对重组质粒进行鉴定。
（2）将经测序验证正确的重组质粒及慢病毒包装质粒，通过Lipofectamine TM2000共转染到293T细胞后收集、提纯、测定滴度。采用慢病毒载体转染法转染至SKOV3细胞中，并建立稳定转染细胞株。
（3）采用Western blot法和Real time PCR法分别检测未转染组、阴性对照组及转染组细胞中WAVE1蛋白和mRNA表达量的变化，验证和筛选WAVE1基因抑制效应显著的稳定转染细胞株。
结果：
（1）成功设计并合成两条WAVE1特异性shRNA，双酶切实验和
DNA测序报告显示，基因重组技术成功构建WAVE1基因RNA干扰慢
病毒载体，测定滴度为2.2×108U/ml。
（2）慢病毒载体介导的WAVE1-shRNA1、WAVE1-shRNA2和阴性对照成功转染SKOV3细胞，采用嘌呤霉素成功筛选获得稳定表达的单克隆细胞株。
（3）通过Western blot法与Real time PCR法检测、验证和筛选，获得WAVE1基因抑制效果显著的稳定转染EOC细胞株SKOV3-Ri1细胞。
结论：成功靶向构建了WAVE1基因的特异性重组质粒。利用慢病毒载体成功筛选获得了WAVE1基因抑制效果显著的卵巢癌稳定转染细胞株，为进一步研究WAVE1恶性生物学行为及其分子机制奠定实验基础。
第三部分
慢病毒介导的WAVE1基因沉默对上皮性卵巢癌细胞恶性行为的影响
目的：探讨WAVE1基因沉默后对SKOV3细胞生长、增殖、粘附和侵袭等恶性生物学行为的影响。
方法：
（1）采用激光共聚焦显微镜观察WAVE1基因沉默前后SKOV3细胞的形态学改变。
（2）Transwell小室检测WAVE1基因沉默前后SKOV3细胞的迁移、侵袭能力变化。
（3）细胞粘附实验分析WAVE1基因沉默前后SKOV3细胞的粘附功能改变。
（4）MTT比色法测定WAVE1基因沉默前后SKOV3细胞的增殖能力改变。
（5）软琼脂克隆形成实验观察WAVE1基因沉默前后SKOV3细胞的群体依赖性和增殖能力变化。
（6）裸鼠皮下移植瘤实验观察WAVE1基因沉默前后SKOV3细胞的成瘤能力变化。
结果：
（1）干扰WAVE1表达能够使EOC细胞形态发生变化：激光共聚焦显微镜观察到，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞呈现去极化，丝状伪足、片状伪足形成能力显著减弱，形态变圆。
（2）干扰WAVE1表达能够抑制EOC细胞侵袭转移能力：Transwell小室迁移实验结果显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞穿过聚碳酸脂膜的迁移细胞数显著减少（P<0.05）。
Transwell小室侵袭实验结果显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞穿过Matrigel的侵袭细胞数显著减少（P<0.05）。
细胞粘附实验显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞的粘附能力显著降低（P<0.05）。
（3）干扰WAVE1表达能够抑制EOC细胞生长增殖的恶性程度：
MTT法检测EOC细胞的增殖结果显示，与阴性对照组和正常对照组相比，在转染后1d、2d、3d、4d和5d，干扰组SKOV3-Ri1细胞生长曲线较平缓，细胞生长速度明显减缓（P<0.05）。
软琼脂克隆形成实验显示，与阴性对照组和正常对照组相比，干扰组SKOV3-Ri1细胞细胞生长速度变慢，克隆形成数目显著减少（P<0.05）。
（4）干扰WAVE1表达能够抑制裸鼠皮下成瘤的恶性行为能力：
与阴性对照组相比，干扰组移植瘤成瘤能力显著减弱，瘤体生长速度缓慢，体积减小。
结论：WAVE1基因沉默后改变了卵巢癌细胞SKOV3的形态变化，显著抑制了SKOV3细胞的增殖能力和侵袭转移能力，反向证实了WAVE1在EOC增殖和侵袭转移恶性行为中的作用，具有作为EOC预防、治疗基因靶点的潜在价值。
第四部分WAVE1参与上皮性卵巢癌恶性行为的分子机制研究
目的：探讨WAVE1参与上皮性卵巢癌增殖和侵袭转移恶性行为的可能分子机制。
方法：
（1）采用HE染色观察裸鼠移植瘤组织形态学变化。
（2）采用免疫组织化学法和Western blot法检测干扰组与阴性对照组移植瘤组织中与增殖、侵袭转移相关蛋白cyclin D1、VEGF、MMP-2、MMP-9和E-cadherin的水平变化。
（3）采用Western blot法检测WAVE1基因沉默前后卵巢癌细胞中与增殖、侵袭转移相关信号转导通路蛋白AKT与p-AKT，p38MAPK与p-p38MAPK，ERK1/2与p-ERK1/2蛋白表达水平变化。
结果：
（1）HE染色后可见，SKOV3-NC组肿瘤细胞失去极性，排列不规则，而SKOV3-Ri1组细胞可见极性，排列相对整齐。
（2）免疫组织化学及Western blot结果均显示，与SKOV3-NC相比，SKOV3-Ri1移植瘤组织中cyclin D1、VEGF、MMP-2、MMP-9表达水平显著降低，而E-cadherin表达水平上升（P<0.05）。
（3）Western blot法检测信号转导通路相关的蛋白结果显示，SKOV3-Ri1细胞中AKT蛋白、p-AKT蛋白及p-p38MAPK蛋白显著低于阴性对照组SKOV3-NC细胞（P<0.05）。而两组中ERK1/2蛋白、p-ERK1/2蛋白及p38MAPK蛋白无明显改变（P>0.05）。
结论：在EOC细胞中，上调的WAVE1可能通过激活PI3K/AKT和p38MAPK信号转导通路，介导其下游肿瘤相关基因参与EOC的恶性行为。WAVE1有可能是PI3K/AKT和p38MAPK信号转导通路潜在的调节因子。
The ovarian malignant cancer, cervical cancer and endometrialcarcinoma are the most commongynecological malignancies.85-90%ofovarian malignant cancer is epithelial ovarian cancer (EOC). EOC is acommongynecological malignancy that is associated with an unfavorableoutcome, and it is the fifth-leading cause of death in females. Worldwide,nearly204,000women are diagnosed, and125,000die due to ovariancancer each year. Seventy-five percent of EOC patients are diagnosed at anadvanced and metastatic stage because of the lack of sensitive screeningtests or early symptoms. To date, the cellular/molecular mechanisms ofEOC metastasis remain poorly understood, even though extensive clinicaland basic research effortshave been undertaken. Identification of novelmolecular markers and the cellular/molecular mechanisms of EOC couldimprove the prediction of metastasis, novel therapeutic methods and furtherunderstanding of EOC progression.
The initial and essential step of cancer cell metastasis is cell migration.Invasive cancer cells must use their remodeled actin cytoskeleton tomigrate through the extracellular matrix (ECM) and enter the blood or lymphatic system. Reorganization of actin filaments is tightly regulated bya variety of proteins which are essential for cell movement. Our previouslystudy using the innovative reverse capture antibody microarray to identifyautoantibody biomarkers in the plasma samples of EOC patients suggesteda significantly elevated expression of Wiskott–Aldrich syndrome proteinfamily verprolin-homologous protein1(WAVE1) in EOC plasma comparedwithhealthy controls. WAVE1, which belongs to Wiskott–Aldrichsyndrome protein (WASP) family protein,has been proposed as acting as anenhancer. Various researchhas found that WAVE1is critical for cancer cellmigration, invasion and metastasis. Down-regμlation of WAVE1has beenfound to be related to decreased invasion of prostate cancer cells, andresμlts sμggest that it might be used as a molecμlar target for preventingcell metastasis. WAVE1protein was overexpressed in malignant melanomacells, which showedhigher Rac activity than non-invasive andnon-metastatic cells. A recent studyhas shown that WAVE1is a novelregulator of apoptosis that is involved in the multidrug resistance ofleukemia cells.however, no studyhas assessed the expression of WAVE1inpatients with EOC or investigated the role of WAVE1in ovarian cancer cellinvasion and metastasis. In the present study, we aimed to examine thefunction and mechanism of WAVE1in malignant behaviors in EOC by thefollowing four parts.
PART ONETHE EXPRESSION AND CLINICAL SIGNIFICATION OF
WAVE1IN EPITHELIAL OVARIAN CANCER
Objectives: This study aims to determine the effect of WAVE1expression and investigate a possible relationship between WAVE1andprognosis in EOC.
Methods:
1. WAVE1protein level was measured in223EOC specimens byimmunohistochemical staining, and the association of WAVE1proteinexpression with clinicopathological characteristics in223cases of invasiveovarian carcinomas was investigated.
2. WAVE1protein level was measured in46EOC specimens byWestern blot, and the association of WAVE1protein expression withclinicopathological characteristics in46cases of invasive ovariancarcinomas was investigated.
3. Survival analysis was performed to assess the correlation betweenWAVE1expression and survival.
4. Expression of WAVE1in ovarian cancer cell lines was evaluated byWestern blot analysis and immunofluorescence.
Results:
1.Immunohistochemical staining showed that WAVE1was over- expressed in EOC compared with samples from a non-invasive ovariantumor and normal ovaries (P<0.05). The expression of WAVE1wassignificantly associated with advanced FIGO stage, poorgrade, serumCa-125and residual tumor size (P<0.05).
2.Western blot analysis showed that WAVE1was overexpressed inEOC compared with samples from a non-invasive ovarian tumor andnormal ovaries (0.930±0.188,0.586±0.098,0.542±0.103, and0.441±0.097,respectively)(P<0.05). The expression of WAVE1was significantlyassociated with advanced FIGO stage, poorgrade, serum Ca-125andresidual tumor size (P<0.05).
3.Survival analysis showed that patients with low WAVE1staininghada significantly better survival compared to patients withhigh WAVE1staining (P<0.05). In multivariate analysis, WAVE1overexpression,advanced stage and suboptimal surgical debulking were independentprognostic factors of poor survival.
4.By Western blot analysis, WAVE1expression was detected in fourovarian cancer cell lines (1.218±0.112,1.111±0.084,1.057±0.148, and0.968±0.055, respectively). Immunofluorescence was performed todemonstrate WAVE1expression in SKOV3and3AO cell lines.
Conclusions: Our present study finds that WAVE1overexpression isassociated with an unfavorable prognosis. WAVE1is an independentprognostic factor for EOC, which suggests that it is a novel and crucial
predictor for EOC metastasis.
PART TWOCONSTRUCTION OF SHRNA LENTIVIRAL VECTORTARGETING WAVE1GENE AND SELECTION A STABLYTRANSFECTED EPITHELIAL OVARIAN CANCER CELLLINE
Objectives: This study aims to construct short hairpin RNA (shRNA)lentiviral vector targeting WAVE1gene and select a stably transfectedepithelial ovarian cancer cell line for the following studies.
Methods:
1.Designed and synthesized two WAVE1specific shRNA sequencesand one negative control sequence. Double restriction digestion and DNAsequencing were used to identified the recombinant plasmid.
2.The correct recombinant plasmid and lentiviral vector wereco-transfected into293T cells by Lipofectamine TM2000to collect andpurify lentivirus virus particles. Establishing stably transfected epithelialovarian cancer cell lines by the manufacturer’s protocol.
3.Identified the best inhibited effect of WAVE1in the stablytransfected epithelial ovarian cancer cell lines by western blot and real time PCR
Results:
1.The double restriction digestion and DNA sequencing showed wesuccessfully designed and synthesized two WAVE1specific shRNAsequences, with a titer of2.2×108U/ml.
2.According to the manufacturer’s protocol, we established stablytransfected ovarian cancer cell lines by puromycin.
3.The western blot and Real time PCR showed the protein and mRNAlevels of WAVE1were down-regulated in stably transfected ovarian cancercell lines. The SKOV3-Ri1cell line was with the more inhibited effect ofWAVE1.
Conclusions: Our present study successfully designed andsynthesized two WAVE1specific shRNA sequences. By lentivirus vector,weharvested the stably transfected epithelial ovarian cancer cell lineSKOV3-Ri1with the more inhibited effect of WAVE1.
PART THREEWAVE1GENE SILENCING VIA RNA INTERFERENCEIMPACT ON THE MALIGNANT BEHAVIOR OFEPITHELIAL OVARIAN CANCER CELLS
Objectives: This study aims to investigate the effect of WAVE1genesilencing via RNA interference impact on the proliferation, migration,invasion, and adhesion in SKOV3cells.
Methods:
1.The morphplogic changes of SKOV3cells before and afterinhibition of WAVE1were detected by confocal immunofluorescencemicroscopy.
2.The cell migration and invasion of SKOV3cells before and afterinhibition of WAVE1were analyzed by transwell assay.
3.The cell adhesion of SKOV3cells before and after inhibition ofWAVE1was tested by cell adhesion assay.
4.The cell proliferation of SKOV3cells before and after inhibition ofWAVE1was investigated by MTT assay.
5.The cell anchorage-independentgrowth of SKOV3cells before andafter inhibition of WAVE1was examined by soft agar assay.
6.The tumor formation of SKOV3cells before and after inhibition ofWAVE1was measured in nude mice.
Results:
1.WAVE1silencing induces morphologic changes:
The morphology of the SKOV3-Ri1, SKOV3-NC and SKOV3were examined using actin staining. The SKOV3-Ri1was unpolarized, missingtheir pseudopodia, presented reduced cellular protrusions, and wasreshaped compared with control cells.
2.WAVE1silencing decreases cell migration and invasion:
Transwell assays were carried out to determine the effects of WAVE1silencing on ovarian cancer cell migration and invasion. In SKOV3-Ri1, asignificant reduction in the number of migratory cells was observedcompared with the control cells (P<0.05), and there was also a significantdecrease in the number of invading cells compared with the control cells.
The SKOV3-Ri1presented a significant decrease in cell adhesioncompared with the control cells (P<0.05).
3.WAVE1silencing inhibits colony formation and cell proliferation:
Using the MTT assay, we found that SKOV3-Ri1presented asignificantgrowth-inhibiting effect on day2(P<0.05).
Using a soft agar assay, we found that the average number of coloniesformed by SKOV3-Ri1was significantly lower than the number formed bycontrol cells, and the size of the colonies was reduced (P<0.05).
4.WAVE1silencing inhibits tumor formation in xenografts in nudemice
We found that not only thegrowth rate but also the size of thexenografts of SKOV3-Ri1were significantly slower and smaller,respectively, compared with control cells.
Conclusions: Our present study showed the down-regulation ofWAVE1had a significant effect on cell morphological changes. WAVE1silencing decreased cell migration, cell invasion, cell adhesion, colonyformation and cell proliferation in vitro. In addition, we also found thatdown-regulation of WAVE1inhibited tumor malignant behaviors in vivo.
PART FOURTHE UNDERLYING MECHANISMS OF WAVE1REGULATING THE MALIGNANT BEHAVIOR OFEPITHELIAL OVARIAN CANCER
Objectives: This study aims to investigate the underlying mechanismsof WAVE1regulating proliferative and invasive malignant behaviors ofepithelial ovarian cancer.
Methods:
1.HE staining was used to analyze the morphological changes ofxenografts which formed by SKOV3-Ri1and SKOV3-NC.
2.Immunohistochemical staining and western blot analysis were usedto detect the levels of cyclin D1, VEGF, MMP-2, MMP-9, and E-cadherinin xenografts which formed by SKOV3-Ri1and SKOV3-NC.
3.Western blot analysis were used to examine proliferation-related signaling pathways that regulate cancer cell tumorigenesis and metastasis.The protein level of AKT, p-AKT, p38MAPK, p-p38MAPK, ERK1/2, andp-ERK1/2were tested in SKOV3-Ri1cells and SKOV3-NC.
Results:
1.HE staining showed the morphology of SKOV3-Ri1changed.
2.Immunohistochemical staining and western blot analysis showed thedown-regulation of WAVE1, MMP-2, MMP-9, VEGF, and cyclin D1expression, and the up-regulation of E-cadherin expression, were observedin xenografts formed by SKOV3-Ri1, compared with controls.
3.Western blot analysis indicated that total AKT, phospho-AKT, andphospho-p38protein levels were down-regulated in SKOV3-Ri1. Incontrast, no WAVE1silencing-induced changes were observed in totalERK1/2, phospho-ERK1/2, and p38levels.
Conclusions: Our present study showed WAVE1regulated themalignant behavior of epithelial ovarian cancer might through theactivation of the PI3K/AKT and p38MAPK signaling pathways.
引文
[1] Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010[J].CA Cancer J Clin.2010,60(5):277-300
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J].Rev Obstetgynecol.2011,4(1):15-21
[3] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[4] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies[J]. Lancet.2007,369(9574):1742-57
[5] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[6]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[7] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[8] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[9] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008;180(4):1515-21
[10] Yang MH, Zhao MY,he YL, et al.Interaction of WAVE1andgenes involved inmultiple drug resistance in children with acute myeloblasticleukemia[J].Zhonghua Er Ke Za Zhi.2010;48(3):175-9
[11] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement. J Cell Sci.2001，114(10):1801-9
[12] Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting themembrane to the cytoskeleton. Nat Rev Mol Cell Biol.2007,8(1):37-48
[13] Au CW, Siu MK, Liao X, et al. Tyrosine kinase B receptor and BDNF expressi-on in ovarian cancers-Effect on cell migration, angiogenesis and clinical out-come[J]. Cancer Lett.2009,281(2):151-61
[14] S. Burns,g.O. Cory, W. Vainchenker, et al. Mechanisms ofWASP-mediatedhaematological and immunological disease[J]. Blood.2004,104:3454–62
[15] A.gautreau,h.Y.ho, J. Li, et al. Purification and architecture of the ubiquito-usWAVE complex[J]. Proc. Natl. Acad. Sci. U. S. A.2004,101:4379–83
[16]周敏.应用反向捕获抗体芯片技术筛选子宫内膜异位症和上皮性卵巢癌血清自身抗体［D］.重庆：重庆医科大学，2011
[17] Kurisu S, Takenawa T.WASP and WAVE family proteins: friends or foes incancer invasion[J]? Cancer Sci.2010;101(10):2093-104.
[18] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regulation ofWAVE1-induced actin nucleation by Rac1and Nck[J].Nature.2002,418(6899):790-3
[19] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[20] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[21]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[22]康睿,曹励之,俞燕等. WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[1] Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010[J]. CA Cancer J Clin.2010,60(5):277-300
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J]. Rev Obstetgynecol.2011,4(1):15-21
[3]徐意瑶,卢欣,赵海涛等.卵巢癌肝转移的外科治疗[J].中华临床医师杂志（电子版）.2010,4(6):797-9
[4]崔恒.卵巢癌的诊治及其研究策略[J].中国妇产科临床杂志.2006,7(5):323-6
[5] Al Rawahi T, Lopes AD, Bristow RE, et al. Surgical cytoreduction for recurrentepithelial ovarian cancer[J]. Cochrane Database Syst Rev.2013, doi:10.1002/14651858.
[6] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011;15;71(2):349-59.
[7] Chambers SK, Clouser MC, Baker AF, Roe DJ,et al.Overexpression of tumorvascular endothelialgrowth factor A may portend an increased likelihood ofprogression in a phase II trial of bevacizumab and erlotinib in resistant ovariancancer[J].Clin Cancer Res.2010;1;16(21):5320-8.
[8] Lu L, Schwartz P, Scarampi L,et al. MicroRNA let-7a: a potential marker forselection of paclitaxel in ovarian cancer management[J].gynecol Oncol.2011,122(2):366-71.
[9] Noske A, Kaszubiak A, Weichert W, et al. Specific inhibition of AKT2by RNAinterference results in reduction of ovarian cancer cell proliferation: increasedexpression of AKT in advanced ovarian cancer[J].Cancer Lett.2007,246(1-2):190-200.
[10] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[11]周敏.应用反向捕获抗体芯片技术筛选子宫内膜异位症和上皮性卵巢癌血清自身抗体［D］.重庆：重庆医科大学，2011
[12] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes[J]. Wound RepairRegen.2010,18(6):594-604
[13] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008;18;582(14):2102-11.
[14] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[15] Sarmiento C, Wang W, Dovas A,et al. WASP family members and formin proteinscoordinate regulation of cell protrusions in carcinoma cells[J]. J Cell Biol.2008;24;180(6):1245-60.
[16]贺钰磊,曹励之,杨静等.急性淋巴细胞白血病患儿WAVE1和p22phox的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志.2009,11(2):88-92
[17]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[18] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[19] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved in theinvasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[20] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies[J]. Lancet.2007,369(9574):1742-57
[21] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[22]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[23] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[24] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[25] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008;180(4):1515-21
[26] Yang MH, Zhao MY,he YL, et al.Interaction of WAVE1andgenes involved inmultiple drug resistance in children with acute myeloblasticleukemia[J].Zhonghua Er Ke Za Zhi.2010;48(3):175-9
[27] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regμlation of WAVE1-induced actin nucleation by Rac1and Nck[J].Nature.2002,418(6899):790-3
[28] S. Burns,g.O. Cory, W. Vainchenker, et al. Mechanisms of WASP-mediatedha-ematological and immunological disease[J]. Blood.2004,104:3454–62
[29] A.gautreau,h.Y.ho, J. Li, et al. Purification and architecture of the ubiquito-usWAVE complex[J]. Proc. Natl. Acad. Sci. U. S. A.2004,101:4379–83
[30] Mikih, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involvedin actin reorganization induced by Rac[J]. EMBO J.1998,17(23):6932-41
[31] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement[J]. J Cell Sci.2001,114(10):1801-9
[32] Suetsugu S, Yamazaki D, Kurisu S, et al. Differential roles of WAVE1andWAVE2in dorsal and peripheral ruffle formation for fibroblast cell migration [J].Dev Cell.2003,5(4):595-609
[33] Suetsugu S, Mikih, Takenawa T. Identification of twohuman WAVE/SCAR-homologues asgeneral actin regulatory molecules which associate with the Arp2/3complex[J]. Biochem Biophys Res Commun.1999,260(1):296-302
[34] FernandohS, Davies SR, Chhabra A, et al. Expression of the WASP verprolin-homologues(WAVE members) inhuman breast cancer[J]. Oncology.2007,73(5-6):376-83
[35]贺钰磊,曹励之,杨明华等. WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[36] Yang LY, Tao YM, Ou DP, et al. Increased expression of Wiskott-Aldrichsyndrome protein family verprolin-homologous protein2correlated with poorprognosis ofhepatocellular carcinoma[J].Clin Cancer Res.2006,12(19):5673-9
[37] Iwaya K, Norio K, Mukai K. Coexpression of Arp2and WAVE2predicts pooroutcome in invasive breast carcinoma[J]. Mod Pathol.2007,20(3):339-43
[38] Chinni SR, Falchetto R,gercel-Taylor C, et al.humoral immune responses tocathepsin D andglucose-regulated protein78in ovarian cancer patients[J]. ClinCancer Res1997,3(9):1557–64.
[39] Korneeva I, Bongiovanni AM,girotra M, et al. Serum antibodies to the27-kdheatshock protein in women withgynecologic cancers[J]. Am J Obstetgyne-col2000,183(1):18–21.
[40] Tong YQ, Liu B, ZhenghY,et al. BMI-1autoantibody as a new potentialbiomarker for cervical carcinoma[J]. PLoS One.2011;6(11):e27804
[41] Chang W, Wu L, Cao F, et al. Development of autoantibody signatures asbiomarkers for early detection of colorectal carcinoma[J]. Clin Cancer Res.2011,17(17):5715-24
[42] Solassol J, Harmand PO, Maudelonde T, et al. Autoantibodies against tumor-related antigens: new tools for early detection of lung cancer[J]. Bull Cancer.2011,98(12):1419-30
[1] Castel SE, Martienssen RA. RNA interference in the nucleus: roles for smallRNAs in transcription, epigenetics and beyond[J]. Nat Revgenet.2013,14(2):100-12
[2] Lambeth LS, Smith CA. Short hairpin RNA-mediatedgene silencing[J]. MethodsMol Biol.2013,942:205-32
[3]陈湘琦,李志鹰,林挺岩. RNA干扰技术在肺癌基因治疗中的应用研究现状[J].中华临床医师杂志.2010,4(7):1028-31
[4]刘文康,王华,苍金荣等.特异性siRNA抑制宫颈癌细胞中iASPP基因的表达研究[J].现代检验医学杂志.2012,27(6):11-4
[5]宋清源生秀杰周冬梅等.RNA干扰沉默基质金属蛋白酶2基因对卵巢癌OVCAR-3细胞诱导体外血管形成能力的影响[J].肿瘤研究与临床.2012,12:793-6
[6] Wang C, Navab R, Iakovlev V, et al. Abelson interactor protein-1positivelyregulates breast cancer cell proliferation, migration, and invasion[J].Mol CancerRes.2007,5(10):1031-9
[7]段海霞,李东红,马向东.化学合成siRNA对卵巢癌SKOV3细胞中STA33基因表达的抑制作用[J].现代肿瘤医学.2012,20(8):1541-6
[8] Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutictarget for metastatic ovarian cancer[J].Cancer Res.2010,70(19):7570-9
[9] Wang J, Che YL, Lig, et al. Crk and CrkL present with different expression andsignificance in epithelial ovarian carcinoma[J].Mol Carcinog.2011,50(7):506-15
[10]林锐,张旭东.慢病毒介导的mcl-1-shRNA对食管癌细胞生长和化疗敏感性影响[J].临床与实验病理学杂志.2013,29(1):23-8
[11] Wangh, Linghuh, Wang J, et al. The role of Crk/Dock180/Rac1pathway in themalignant behavior ofhuman ovarian cancer cell SKOV3[J]. Tumour Biol.2010,31(1):59-67
[12] Chenh, Wu X, Pan ZK, et al. Integrity of SOS1/EPS8/ABI1tri-complexdetermines ovarian cancer metastasis[J]. Cancer Res.2010,70(23):9979-90
[13]丁明霞,李种,左毅刚等.人膀胱癌EJ细胞株CD44基因的小RNA干扰抑制细胞侵袭功能[J].现代泌尿生殖肿瘤杂志.2011,3(6):345-7
[14]贺钰磊,曹励之,杨明华等. WAVE1对K562细胞侵袭能力的影响及其机制研究.中华血液学杂志.2009,30(4):237-41
[15]陈国庆,姚珍薇,漆洪波等.慢病毒载体抑制FOXM1对卵巢癌SKOV3细胞增殖的影响与分子机制[J].细胞与分子免疫学杂志.2012,29-32
[16]王莉,李娜,吴小华.慢病毒介导的RNAi对卵巢癌细胞增殖及间皮素表达的影响[J].中国肿瘤生物治疗杂志.2008,15(2):134-8
[17] Couzin J. Breakthrough of the year. Small RNAs make big splash[J]. Science.2002,298(5602):2296-7
[18] Mroz EA, Rocco JW. RNA interference: natural, experimental, and clinical rolesin cancer biology[J].head Neck.2006,28(12):1132-41
[19] Preall JB, Sontheimer EJ. RNAi: RISCgets loaded. Cell.2005,123(4):543-5
[20] Filipowicz W. RNAi: the nuts and bolts of the RISC machine[J]. Cell.2005,122(1):17-20
[21] Napoli C, Lemieux C, Jorgensen R. Introduction of a Chimeric ChalconeSynthasegene into Petunia Results in Reversible Co-Suppression of homologous-genes in trans[J]. Plant Cell.1990,2(4):279-289
[22] Guo S, Kemphues KJ. par-1, agene required for establishing polarity in C.elegans embryos, encodes a putative Ser/Thr kinase that is asymmetricallydistributed[J]. Cell.1995,81(4):611-20
[23] Fire A, Xu S, Montgomery MK, et al. Potent and specificgenetic interference bydouble-stranded RNA in Caenorhabditis elegans. Nature[J].1998,391(6669):806-11
[24] Bots M, Maughan S, Nieuwland J. RNAi Nobel ignores vitalgroundwork onplants[J]. Nature.2006,443(7114):906
[25] Jorgensen R. Plants, RNAi, and the Nobel Prize[J]. Science.2006,314(5803):1242-3
[26] Shih, Wang J, Wang X, et al. Construction of eukaryotic expression vector ofshort hairpin RNA targetinghuman xylosyltransferase-Igene[J].hua Xi Kou QiangYi Xue Za Zhi.2008,26(2):206-10(in Chinese)
[27]段海霞,李东红,马向东.化学合成siRNA对卵巢癌SKOV3细胞中STA33基因表达的抑制作用[J].现代肿瘤医学.2012,20(8):1541-6
[28]史文天,王言奎,袁月秀等.化学合成siRNA沉默宫颈癌SiHa细胞E6基因表达的进一步研究[J].齐鲁医学杂志.2009,24(4):283-5
[29] Chen Y,huang L. Tumor-targeted delivery of siRNA by non-viral vector: safe andeffective cancer therapy[J]. Expert Opin Drug Deliv.2008,5(12):1301-11
[30] Martínez-Flores F, Jiménez-Orozco FA, Villegas-Castrejónh. Molecular biologyof adenoviral vectors[J]. Cir Cir.2006,74(6):483-93
[31] Witlox MA, Lamfersml, Wuisman PI, et al. Evolvinggene therapy approaches forosteosarcoma using viral vectors: review[J]. Bone.2007,40(4):797-812
[32] Frecha C, Szécsi J, Cosset FL, et al. Strategies for targeting lentiviral vectors[J].Currgene Ther.2008,8(6):449-60
[33] Schambach A, Baum C. Clinical application of lentiviral vectors-concepts andpractice[J]. Currgene Ther.2008,8(6):474-82
[34] Singer O, Verma IM. Applications of lentiviral vectors for shRNA delivery andtransgenesis[J]. Currgene Ther.2008,8(6):483-8
[35] Sumimotoh, Kawakami Y. Lentiviral vector-mediated RNAi and its use forcancer research[J]. Future Oncol.2007,3(6):655-64
[36] Ciuffi A. Mechanismsgoverning lentivirus integration site selection[J]. CurrgeneTher.2008,8(6):419-29
[37] Reynolds A, Leake D, Boese Q, et al. Rational siRNA design for RNAinterference[J]. Nat Biotechnol.2004,22(3):326-30
[38] Gong D, Ferrell JE Jr. Picking a winner: new mechanistic insights into the designof effective siRNAs[J]. Trends Biotechnol.2004,22(9):451-4
[39]康睿,曹励之,俞燕等. WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[40]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[41] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[42] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[1] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J]. Rev Obstetgynecol.2011,4(1):15-21
[3] Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010[J]. CA Cancer J Clin.2010,60(5):277-300
[4] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[5] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[6]崔银江,李少华.E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[7]徐菊玲,邵圣文. Cdc42蛋白与细胞迁移、极化以及细胞骨架调节的关系[J].现代预防医学.2011,38(6):1148-9
[8] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[9] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis[J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[10] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia[J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[11] Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes incancer invasion?[J]. Cancer Sci.2010,101(10):2093-104
[12] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011;15;71(2):349-59.
[13] Chambers SK, Clouser MC, Baker AF, Roe DJ,et al.Overexpression of tumorvascular endothelialgrowth factor A may portend an increased likelihood ofprogression in a phase II trial of bevacizumab and erlotinib in resistant ovariancancer[J].Clin Cancer Res.2010;1;16(21):5320-8.
[14] Lu L, Schwartz P, Scarampi L,et al. MicroRNA let-7a: a potential marker forselection of paclitaxel in ovarian cancer management[J].Gynecol Oncol.2011,122(2):366-71.
[15]龙丽,唐良萏.绿茶提取物表没食子儿茶素3没食子酸酯对人卵巢癌HO-8910细胞增殖及信号通路相关基因表达的影响[J].中国生物制品学杂志.2012,25(9):1165-70
[16]范婷婷,唐良萏.NEK2基因沉默促进卵巢癌细胞SKOV3凋亡[J].基础医学与临床.2012,32(6):664-8.
[17] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[18] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[19]高卫栋,,王红兵,吴泽志等.肿瘤细胞迁移特性及细胞迁移能力表征[J].细胞生物学杂志.2008,30:451-6
[20] Vaňhara P,horak P, Pils D, et al. Loss of the oligosaccharyl transferase subunitTUSC3promotes proliferation and migration of ovarian cancer cells[J]. Int JOncol.2013,42(4):1383-9
[21] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes[J]. Wound RepairRegen.2010,18(6):594-604
[22] Heng JI, Chariot A, Nguyen L. Molecular layers underlying cytoskeletalremodeling during cortical development[J]. Trends Neurosci.2010,33(1):38-47
[23] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[24] Chi X, Wang S,huang Y, et al. Roles of rhogTPases in intracellular transport andcellular transformation[J]. Int J Mol Sci.2013,14(4):7089-108
[25] Oda A, Eto K. WASPs and WAVEs: From molecular function to physiologyinhematopoietic cells[J]. Semin Cell Dev Biol.2013,14. doi: S1084-9521(13)00029-3.
[26] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia[J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[27] Takahashi K, Suzuki K. WAVE2, N-WASP, and Mena facilitate cell invasion viaphosphatidylinositol3-kinase-dependent local accumulation of actin filaments[J]. J Cell Biochem.2011,112(11):3421-9
[28] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis[J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[29] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[30]贺钰磊,曹励之,杨明华等.WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[31] Hale JS, Li M, Lathia JD.The malignant social network: cell-cell adhesion andcommunication in cancer stem cells[J].Cell Adh Migr.2012,6(4):346-55
[32] Lampugnanimg. Endothelial cell-to-cell junctions: adhesion and signaling inphysiology and pathology[J].Cold Springharb Perspect Med.2012,2(10).
[33] Carneiro P, Fernandes MS, Figueiredo J, et al. E-cadherin dysfunction ingastriccancer--cellular consequences, clinical applications and open questions[J]. FEBSLett.2012,586(18):2981-9
[34] Sampieri K, Fodde R. Cancer stem cells and metastasis[J]. Semin Cancer Biol.2012,22(3):187-93.
[35] Kohn EC,hurteau J.Ovarian cancer: making its own rules-again[J]. Cancer.2013,119(3):474-6
[36] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011,71(2):349-59
[37] Zha L, Zhang J, Tang W, et al.HMGA2Elicits EMT by Activating theWnt/β-catenin Pathway ingastric Cancer[J]. Dig Dis Sci.2013,58(3):724-33
[38] Chen WC, Kuo TH, Tzeng YS, et al. Baicalin induces apoptosis in SW620humancolorectal carcinoma cells in vitro and suppresses tumorgrowth in vivo[J].Molecules.2012,17(4):3844-57
[39] Schou M, Brünner N, Spang-Thomsen M, et al. Mendelian analysis of ametastasis-prone substrain of BALB/c nude mice using a subcutaneouslyinoculatedhuman tumour[J]. APMIS.2006,114(12):899-907
[40] Brom M, Joosten L, Oyen WJ, et al. RadiolabelledgLP-1analogues for in vivotargeting of insulinomas[J]. Contrast Media Mol Imaging.2012,7(2):160-6
[1] Wade M, Li YC, WahlgM. MDM2, MDMX and p53in oncogenesis and cancertherapy[J]. Nat Rev Cancer.2013,13(2):83-96
[2] Muller PA, Vousden KH. p53mutations in cancer[J]. Nat Cell Biol.2013,15(1):2-8
[3]郭锐,雷小勇. miRNA靶位点SNP与肿瘤发生及其药物敏感性研究进展[J].中南医学科学杂志.2013,41(1):89-93
[4]杨光,裘正军.信号传导通路与肿瘤侵袭和转移机制的研究进展[J].现代肿瘤医学.2009,17(2):362-4
[5]张晔,刘云鹏.PI3K/Akt信号传导通路与肿瘤[J].中华临床医师杂志（电子版）.2010,10(20):96-9
[6]魏小勇,黎才海,饶荣生.p38MAPK信号通路与肿瘤的关系[J].实用癌症杂志.2009,24(1):101-3
[7] Kohn EC,hurteau J.Ovarian cancer: making its own rules-again[J]. Cancer.2013,119(3):474-6
[8] Leary A, Pautier P, Tazi Y, et al. The molecular biology of epithelial ovariancancer[J]. Bull Cancer.2012,99(12):1161-73
[9] Zhaoh, Yang Z, Wang X, et al. Triptolide inhibits ovarian cancer cell invasion byrepression of matrix metalloproteinase7and19and upregulation ofE-cadherin[J]. Exp Mol Med.2012,44(11):633-41
[10] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[11]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[12] Canel M, Serrels A, Frame MC, et al. E-cadherin-integrin crosstalk in cancerinvasion and metastasis[J]. J Cell Sci.2013,126(Pt2):393-401
[13] Colas E, Pedrola N, Devis L, et al. The EMT signaling pathways in endometrialcarcinoma[J]. Clin Transl Oncol.2012,14(10):715-20
[14] Mell LK, Meyer JJ, Tretiakova M, et al.Prognostic significance of E-cadherinprotein expression in pathological stage I-III endometrial cancer[J]. Clin CancerRes.2004,10(16):5546-53
[15] Nagathihalli NS, Merchant NB. Src-mediated regulation of E-cadherin and EMTin pancreatic cancer[J]. Front Biosci.2012,17:2059-69
[16]徐洪涛,王恩华.E钙粘蛋白-环连蛋白复合体与肿瘤[J].国外医学：肿瘤学分册.2004,31(2):107-110
[17] Ba i B,hallerh, Mrkli I, et al. Prognostic role of E-cadherin in patients withadvanced serous ovarian cancer[J]. Archgynecol Obstet.2012, Epub ahead ofprint, PMID:23269354
[18] Ta kin S, Dünder I, Erol E, et al.Roles of E-cadherin and cyclooxygenaseenzymes in predicting different survival patterns of optimally cytoreduced serousovarian cancer patients[J]. Asian Pac J Cancer Prev.2012,13(11):5715-9
[19] PenghL,he L, Zhao X. Association of reduced immunohistochemical expressionof E-cadherin with a poor ovarian cancer prognosis--results of a meta-analysis[J].Asian Pac J Cancer Prev.2012,13(5):2003-7
[20] Knapinska A, FieldsgB. Chemical biology for understanding matrixmetalloproteinase function[J]. Chembiochem.2012,13(14):2002-20
[21] Bartlett JD, Smith CE. Modulation of cell-cell junctional complexes by matrixmetalloproteinases[J]. J Dent Res.2013,92(1):10-7
[22]董颖,赵长宏.基质金属蛋白酶与肿瘤侵袭转移的研究进展[J].实用肿瘤学杂志.2007,21(4):384-6
[23]孙春凤,黄国平,陈克平.基质金属蛋白酶-2的结构和功能[J].安徽医科大学学报.2013,48(3):330-2
[24] Rundhaug JE. Matrix metalloproteinases and angiogenesis[J]. J Cell Mol Med.2005,9(2):267-85
[25] Siefert SA, Sarkar R. Matrix metalloproteinases in vascular physiology anddisease Vascular[J].2012,20(4):210-6
[26] Lih,huang D,gao Z, et al. Scutellarin inhibits thegrowth and invasion ofhumantongue squamous carcinoma through the inhibition of matrix metalloproteinase-2and-9and αvβ6integrin[J]. Int J Oncol.2013,42(5):1674-81
[27] Laios A, Mohamed BM, Kelly L, et al. Pre-Treatment of Platinum ResistantOvarian Cancer Cells with an MMP-9/MMP-2Inhibitor Prior to CisplatinEnhances Cytotoxicity as Determined byhigh Content Screening[J]. Int J Mol Sci.2013,14(1):2085-103
[28] Hu X, Li D, Zhang W, et al. Matrix metalloproteinase-9expression correlateswith prognosis and involved in ovarian cancer cell invasion[J]. ArchgynecolObstet.2012,286(6):1537-43
[29] Noh S, Jung JJ, Jung M, et al. Body fluid MMP-2as a putative biomarker inmetastatic breast cancer[J]. Oncol Lett.2012,3(3):699-703
[30] Puljiz M, Puljiz Z, Vucemilo T, et al. Prognostic significance of matrixmetalloproteinases2and9in endometrial cancer. Coll Antropol[J].2012,36(4):1367-72
[31]王前,邓晶,蒋永新. cyclin D1的研究进展[J].现代肿瘤医学.2009,17(2):350-3
[32]贾文娟,李胜泽.STAT3、cyclin D1在妇科肿瘤中的研究进展[J].蚌埠医学院学报.2009,34(2):182-4
[33]王福生.周期素D1与肿瘤研究进展[J].国外医学：临床生物化学与检验学分册.2000,21(3):140-1
[34] Li N, Zhong X, Lin X, et al. Lin-28homologue A (LIN28A) promotes cell cycleprogression via regulation of cyclin-dependent kinase2(CDK2), cyclin D1(CCND1), and cell division cycle25homolog A (CDC25A) expression incancer[J]. J Biol Chem.2012,287(21):17386-97
[35] Ashrafi M, Bathaie SZ, Abroun S.high Expression of Cyclin D1and p21inN-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats[J]. Cell J.2012,14(3):193-202
[36] Lin S, YuhS. Clinical significance of nucleostemin expression and its correlationwith cyclin D1expression in malignant ovarian tumors[J]. Int Jgynecol Cancer.2011,21(7):1166-71
[37]田冬艳,王德华,刘永红. Survivin和Cyclin D1在卵巢癌中的表达和相关性[J].天津医科大学学报.2009,15(1):81-3
[38]Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors inregulation of angiogenesis and lymphangiogenesis[J]. Exp. Cell. Res.2006,312(5):549-60
[39]Takahashih, Shibuya, M. The vascular endothelialgrowth factor (VEGF)/VEGFreceptor system and its role under physiological and pathological conditions[J].Clin Sci.2005,109(3),227～241.
[40] Yu L, Deng L, Li J, et al. The prognostic value of vascular endothelialgrowthfactor in ovarian cancer: a systematic review and meta-analysis[J].gynecol Oncol.2013,128(2):391-6
[41]李慧玲,苏亚娟,邬剑等.MMP-2、VEGF在卵巢癌组织中的表达及其临床意义[J].中国实验诊断学.2009,13(6):726-9
[41]曾晓林,彭耀金. VEGF、MMP-2与MMP-9在卵巢癌组织中的表达及其临床意义[J].现代生物医学进展.2010,10(12):2322-4
[42]蔡冬燕,韩凤娟,闫忠鑫等.VEGF表达与卵巢癌相关性的研究进展[J].世界中西医结合杂志.2012,7(12):1091-3
[43]张洪英,陈军宝,卢宏柱.PI3K/Akt信号通路在肿瘤血管形成中的作用研究进展[J].山东医药.2012,52(47):98-100
[44]胡蕾,姜汉国.PI3K／AKT信号传导通路与肿瘤转移及其机制的研究进展[J].医学综述.2006,12(22):1375-7
[45]徐林林,梅金红.丝裂原活化蛋白激酶信号通路与卵巢癌关系的研究进展[J].实用癌症杂志.2007,22(5):540-2
[46] Zhu C, Qi X, Chen Y, et al. PI3K/Akt and MAPK/ERK1/2signaling pathways areinvolved in IGF-1-induced VEGF-C upregulation in breast cancer[J]. J CancerRes Clin Oncol.2011,137(11):1587-94
[47] Chang MC, Chen CA, Chen PJ, et al. Mesothelin enhances invasion of ovariancancer by inducing MMP-7through MAPK/ERK and JNK pathways[J]. BiochemJ.2012,442(2):293-302.
[48] Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL, et al. Oppositeregulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression,cell-associated procoagulant activity and invasiveness in MDA-MB-231cells [J].Jhematol Oncol.2012,5(1):16.
[49] Reuben PM, CheunghS. Regulation of matrix metalloproteinase (MMP)geneexpression by protein kinases[J]. Front Biosci.2006,11:1199-215
[50] Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediatesinsulin-likegrowth factor1-induced E-cadherin down-regulation and cellproliferation in ovarian cancer cells[J]. Cancer Lett.2012,326(2):191-8.
[1] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies [J]. Lancet.2007,369(9574):1742-57
[2] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility [J]. Annu Rev Cell Dev Biol.2005,21:695-18
[3] Machesky LM. Lamellipodia and filopodia in metastasis and invasion [J]. FEBSLett.2008,582(14):2102-11
[4] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion [J].Cancer Metastasis Rev.2009,28(1-2):15-33
[5]崔银江,李少华. E-钙粘附素的研究进展.中国矫形外科杂志.2009,17(13):1001-3
[6] Kedrin D, van Rheenen J,hernandez L, et al. Cell motility and cytoskeletalregulation in invasion and metastasis [J]. J Mammarygland Biol Neoplasia.2007,12(2-3):143-52
[7] Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility [J]. Clin ExpMetastasis.2009,26(4):273-87
[8]高卫栋,王红兵,吴泽志等.肿瘤细胞迁移特性及细胞迁移能力表征[J].细胞生物学杂志.2008,30(4):451-6
[9] Vaňhara P,horak P, Pils D, et al. Loss of the oligosaccharyl transferase subunitTUSC3promotes proliferation and migration of ovarian cancer cells [J]. Int JOncol.2013,42(4):1383-9
[10] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes [J]. Wound RepairRegen.2010,18(6):594-604
[11] Yamaguchih, Condeelis J. Regulation of the actin cytoskeleton in cancer cellmigration and invasion[J]. Biochim Biophys Acta.2007,1773(5):642-52
[12]周方正,伍钢.细胞伪足与肿瘤转移研究进展[J].临床肿瘤学杂志.2007,12(1):77-9
[13] Heng JI, Chariot A, Nguyen L. Molecular layers underlying cytoskeletalremodeling during cortical development [J]. Trends Neurosci.2010,33(1):38-47
[14] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[15] Chi X, Wang S,huang Y, et al. Roles of rhogTPases in intracellμlar transport andcellμlar transformation [J]. Int J Mol Sci.2013,14(4):7089-108
[16] Oda A, Eto K. WASPs and WAVEs: From molecμlar function to physiologyinhematopoietic cells [J]. Semin Cell Dev Biol.2013,14. doi: S1084-9521(13)00029-3.
[17] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia [J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[18] Takahashi K, Suzuki K. WAVE2, N-WASP, and Mena facilitate cell invasion viaphosphatidylinositol3-kinase-dependent local accumulation of actin filaments[J]. J Cell Biochem.2011,112(11):3421-9
[19] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis [J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[20] Massaad MJ, Ramesh N,geha RS. Wiskott-Aldrich syndrome: a comprehensivereview[J]. Ann N Y Acad Sci.2013,. doi:10.1111/nyas.12049.
[21] Notarangelo LD, Miao CH, OchshD, et a1. Wiskott-Aldrich syndrome [J]．CurrOpinhematol,2008,15(1):30-6
[22] Derry JM, OchshD, Francke U: Isolation of a novelgene mutated inWiskott-Aldrich syndrome [J]. Cell.1994,78(4):635-44.
[23] Mikih, Miura K, Takenawa T. N-WASP, a novel actin-depolymerizing protein,regulates the cortical cytoskeletal rearrangement in a PIP2-dependent mannerdownstream of tyrosine kinases[J]. EMBO J.1996,15(19):5326-35
[24] Mikih, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involvedin actin reorganization induced by Rac[J]. EMBO J.1998,17(23):6932-41
[25] Suetsugu S, Mikih, Takenawa T. Identification of twohuman WAVE/SCAR-homologues asgeneral actin regulatory molecules which associate with theArp2/3complex[J]. Biochem Biophys Res Commun.1999,260(1):296-302
[26]张利军,魏蕾. WAVE2与细胞骨架的研究进展[J].武汉大学学报：医学版.2005,26(5):678-682
[27] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement[J]. J Cell Sci.2001,114(10):1801-9
[28] Vartiainen MK, Machesky LM. The WASP-Arp2/3pathway:genetic insights[J].Curr Opin Cell Biol.2004,16(2):174-81
[29] Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting themembrane to the cytoskeleton[J]. Nat Rev Mol Cell Biol.2007,8(1):37-48
[30] Rohatgi R,hohY, Kirschner MW. Mechanism of N-WASP activation by CDC42and phosphatidylinositol4,5-bisphosphate[J]. J Cell Biol.2000,150(6):1299-310
[31] Mikih, Yamaguchih, Suetsugu S, et a1. IRSp53is an essential intermediatebetween Rac and WAVE in the regulation of membrane ruffling[J]. Nature.2000,408(6813):732-5
[32] Soderling SH, Binns KL, WaymangA, et al. The WRP component of the WAVE-1complex attenuates Rac-mediated signalling[J]. Nat Cell Biol.2002,4(12):970-5
[33] Gautreau A,hohY, Li J, et al. Purification and architecture of the ubiquitous Wavecomplex[J]. Proc Natl Acad Sci U S A.2004,101(13):4379-83
[34] Echarri A, Lai MJ, Robinson MR, et al. Abl interactor1(Abi-1) wave-bindingand SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodiumlocalization, and wave-1levels[J]. Mol Cell Biol.2004,24(11):4979-93
[35] Innocenti M,gerboth S, Rottner K, et al. Abi1regulates the activity of N-WASPand WAVE in distinct actin-based processes[J]. Nat Cell Biol.2005,7(10):969-76
[36] Mikih, Takenawa T. WAVE2serves a functional partner of IRSp53by regulatingits interaction with Rac[J]. Biochem Biophys Res Commun.2002,293(1):93-9
[37] Beltzner CC, Pollard TD. Pathway of actin filament branch formation by Arp2/3complex[J]. J Biol Chem.2008,283(11):7135-44
[38] Sirotkin V, Beltzner CC, Marchand JB, et al. Interactions of WASp, myosin-1,and verprolin with Arp2/3complex during actin patch assembly in fission yeast[J]. J Cell Biol.2005,170(4):637-48
[39] Pollard TD, Beltzner CC. Structure and function of the Arp2/3complex[J]. CurrOpin Struct Biol.2002,12(6):768-74
[40] Pollard TD, BorisygG. Cellular motility driven by assembly and disassembly ofactin filaments [J]. Cell,2003,113(4):453-65
[41] Richardson BE, BeckeR K, Scott J, et a1. SCAR/WAVE and Arp2/3are crucialfor cytoskeletal remodeling at the site of myoblast fusion [J]. Development.2007,134(24):4357-67
[42] Yamaguchih, Mikih, Suetsugu S, et al. Two tandem verprolinhomology domainsare necessary for a strong activation of Arp2/3complex-induced actinpolymerization and induction of microspike formation by N-WASP[J]. Proc NatlAcad Sci U S A.2000,97(23):12631-6
[43] de la Fuente MA, Sasahara Y, Calamito M, et al. WIP is a chaperone forWiskott-Aldrich syndrome protein (WASP)[J]. Proc Natl Acad Sci U S A.2007,104(3):926-31
[44] HohY, Rohatgi R, Lebensohn AM, et al. Toca-1mediates Cdc42-dependent actinnucleation by activating the N-WASP-WIP complex[J]. Cell.2004,118(2):203-16
[45] Suetsugu S, Banzai Y, Kato M, et al. Male-specific sterility caused by the loss ofCR16.genes Cells.2007,12(6):721-33
[46] Sawa M, Takenawa T. Caenorhabditis elegans WASP-interacting proteinhomologue WIP-1is involved in morphogenesis through maintenance of WSP-1protein levels[J]. Biochem Biophys Res Commun.2006,340(2):709-17
[47] Volkman BF, Prehoda KE, Scott JA, et al. Structure of the N-WASP EVH1domain-WIP complex: insight into the molecular basis of Wiskott-AldrichSyndrome[J]. Cell.2002,111(4):565-76
[48] Imai K, Nonoyama S, OchshD. WASP (Wiskott-Aldrich syndrome protein)genemutations and phenotype[J]. Curr Opin Allergy Clin Immunol.2003,3(6):427-36
[49] Symons M, Derry JM, Karlak B, et al. Wiskott-Aldrich syndrome protein, a noveleffector for thegTPase CDC42Hs, is implicated in actin polymerization[J]. Cell.1996,84(5):723-34
[50] Kurisu S, Takenawa T. The WASP and WAVE family proteins.genome Biol[J].2009,10(6):226
[51] Innocenti M, Zucconi A, Disanza A, et al. Abi1is essential for the formation andactivation of a WAVE2signalling complex[J]. Nat Cell Biol.2004,6(4):319-27
[52] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regulation ofWAVE1-induced actin nucleation by Rac1and Nck Nature[J].2002,418(6899):790-3
[53] Jenei V, Andersson T, Jakus J, et al. E3B1, ahumanhomologue of the mousegeneproduct Abi-1, sensitizes activation of Rap1in response to epidermalgrowthfactor[J]. Exp Cell Res.2005,310(2):463-73
[54] Suetsugu S, Mikih, Yamaguchih, et al. Enhancement of branching efficiency bythe actin filament-binding activity of N-WASP/WAVE2[J]. J Cell Sci.2001,114(24):4533-42
[55] Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes incancer invasion?[J]. Cancer Sci.2010,101(10):2093-104
[56] Kim AS, Kakalis LT, Abdul-Manan N, et al. Autoinhibition and activationmechanisms of the Wiskott-Aldrich syndrome protein. Nature[J].2000,404(6774):151-8
[57] Prehoda KE, Scott JA, Mullins RD, et al. Integration of multiple signals throughcooperative regulation of the N-WASP-Arp2/3complex[J]. Science.2000,290(5492):801-6
[58] Suetsugu S,hattori M, Mikih, et al. Sustained activation of N-WASP throughphosphorylation is essential for neurite extension[J]. Dev Cell.2002,3(5):645-58
[59] CorygO,garg R, Cramer R,et al. Phosphorylation of tyrosine291enhances theability of WASp to stimulate actin polymerization and filopodium formation.Wiskott-Aldrich Syndrome protein[J]. J Biol Chem.2002,277(47):45115-21
[60] CorygO, Cramer R, Blanchoin L, et al. Phosphorylation of the WASP-VCAdomain increases its affinity for the Arp2/3complex and enhances actinpolymerization by WASP[J]. Mol Cell.2003,11(5):1229-39
[61] Park SJ, Suetsugu S, Takenawa T. Interaction ofhSP90to N-WASP leads toactivation and protection from proteasome-dependent degradation[J]. EMBO J.2005,24(8):1557-70
[62] Cestrag, Toomre D, Chang S, et al. The Abl/Arg substrate ArgBP2/nArgBP2coordinates the function of multiple regulatory mechanisms converging on theactin cytoskeleton[J]. Proc Natl Acad Sci U S A.2005,102(5):1731-6
[63] Rogers SL, Wiedemann U, Stuurman N, et al. Molecular requirements foractin-based lamella formation in Drosophila S2cells[J]. J Cell Biol.2003,162(6):1079-88.
[64]崔梅花,郁卫东. Abl相互作用蛋白-1在肿瘤基础与临床研究中的进展[J].中国现代医学杂志.2011,21(17):2021-5
[65] Steffen A, Rottner K, Ehinger J, et al. Sra-1and Nap1link Rac to actin assemblydriving lamellipodia formation[J]. EMBO J.2004,23(4):749-59
[66] Leng Y, Zhang J, Badour K, et al. Abelson-interactor-1promotes WAVE2membrane translocation and Abelson-mediated tyrosine phosphorylation requiredfor WAVE2activation[J]. Proc Natl Acad Sci U S A.2005,102(4):1098-103
[67]张秀真,吴泽志.细胞伪足形成与微丝骨架研究进展[J].国外医学：临床生物化学与检验学分册.2005,26(4):213-6
[68] Baldassarre M, Pompeo A, Beznoussenkog, et al. Dynamin participates in focalextracellular matrix degradation by invasive cells[J]. Mol Biol Cell.2003,14(3):1074-84
[69] Buccione R, Orth JD, McNiven MA. Foot and mouth: podosomes, invadopodiaand circular dorsal ruffles[J]. Nat Rev Mol Cell Biol.2004,5(8):647-57
[70] Chuang YY, Tran NL, Rusk N, et al. Role of synaptojanin2inglioma cellmigration and invasion[J]. Cancer Res.2004,64(22):8271-5
[71] Linder S, Aepfelbacher M. Podosomes: adhesionhot-spots of invasive cells[J].Trends Cell Biol.2003,13(7):376-85
[72] Linder S, Nelson D, Weiss M, et al. Wiskott-Aldrich syndrome protein regulatespodosomes in primaryhuman macrophages[J]. Proc Natl Acad Sci U S A.1999,96(17):9648-53
[73] Yamaguchih, Lorenz M, Kempiak S, et al. Molecular mechanisms ofinvadopodium formation: the role of the N-WASP-Arp2/3complex pathway andcofilin[J]. J Cell Biol.2005,168(3):441-52
[74] Raftopoulou M,hall A. Cell migration: RhogTPases lead the way[J]. Dev Biol.2004,265(1):23-32
[75] Suetsugu S, Yamazaki D, Kurisu S, et al. Differential roles of WAVE1andWAVE2in dorsal and peripheral ruffle formation for fibroblast cell migration[J].Dev Cell.2003,5(4):595-609
[76] Yamazaki D, Fujiwara T, Suetsugu S, et al. A novel function of WAVE inlamellipodia: WAVE1is required for stabilization of lamellipodial protrusionsduring cell spreading[J]. genes Cells.2005,10(5):381-92
[77] Takenawa T. From N-WASP to WAVE: key molecules for regulation of corticalactin organization[J]. Novartis Found Symp.2005,269:3-10
[78] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved in theinvasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[79] Sossey-Alaoui K, Ranalli TA, Li X, et al. WAVE3promotes cell motility andinvasion through the regulation of MMP-1, MMP-3, and MMP-9expression[J].Exp Cell Res.2005,308(1):135-45
[80] Yang LY, Tao YM, Ou DP, et al. Increased expression of Wiskott-Aldrichsyndrome protein family verprolin-homologous protein2correlated with poorprognosis ofhepatocellular carcinoma[J]. Clin Cancer Res.2006,12(19):5673-9
[81] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[82] FernandohS, Sanders AJ, KynastonhG, et al. WAVE3is associated withinvasiveness in prostate cancer cells[J]. Urol Oncol.2010,28(3):320-7
[83] Cai X, Xiao T, James SY, et al. Metastatic potential of lung squamous cellcarcinoma associated withhSPC300through its interaction with WAVE2[J]. LungCancer.2009,65(3):299-305
[84] Semba S, Iwaya K, Matsubayashi J, et al. Coexpression of actin-related protein2and Wiskott-Aldrich syndrome family verproline-homologous protein2inadenocarcinoma of the lung[J]. Clin Cancer Res.2006,12(8):2449-54
[85]康睿,曹励之,俞燕等. WAVE1基因在K562／A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[86]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[87]贺钰磊,曹励之,杨明华等.WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[88]贺钰磊,曹励之,杨静等.急性淋巴细胞白血病患儿WAVE1和p22phox的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志.2009,11(2):88-92
[89]杨明华,赵明一,贺钰磊等.儿童急性髓细胞性白血病WAVE1基因对耐药相关基因表达影响的研究[J].中华儿科杂志.2010,48(3):175-9
[90]1waya K, Oikawa K, Semba S, et a1. Correlation between liver metastasis of thecolocalization of actin-related protein2and3complex and WAVE2in colorectalcarcinoma[J].Cancer Sci.2007,98(7):992-9
[91] FernandohS, Davies SR, Chhabra A, et al. Expression of the WASPverprolin-homologues (WAVE members) inhuman breast cancer[J]. Oncology.2007,73(5-6):376-83
[92] Iwaya K, Norio K, Mukai K. Coexpression of Arp2and WAVE2predicts pooroutcome in invasive breast carcinoma[J]. Mod Pathol.2007,20(3):339-43
[93] Sossey-Alaoui K, Safina A, Li X, et al. Down-regulation of WAVE3, a metastasispromotergene, inhibits invasion and metastasis of breast cancer cells[J]. Am JPathol.2007,170(6):2112-21
[94] Martin TA, Pereirag, Watkinsg, et al. N-WASP is a putative tumour suppressor inbreast cancer cells, in vitro and in vivo, and is associated with clinical outcome inpatients with breast cancer[J]. Clin Exp Metastasis.2008,25(2):97-108
[95]黄琰菁,于世英,王江玲等.乳腺癌中Abi1和c-Abl及WAVE2的表达及其相互关系[J].中国组织化学与细胞化学杂志.2010,19(3):216-20
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J].Rev Obstetgynecol.2011,4(1):15-21
[3] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[4] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies[J]. Lancet.2007,369(9574):1742-57
[5] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[6]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[7] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[8] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[9] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008;180(4):1515-21
[10] Yang MH, Zhao MY,he YL, et al.Interaction of WAVE1andgenes involved inmultiple drug resistance in children with acute myeloblasticleukemia[J].Zhonghua Er Ke Za Zhi.2010;48(3):175-9
[11] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement. J Cell Sci.2001，114(10):1801-9
[12] Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting themembrane to the cytoskeleton. Nat Rev Mol Cell Biol.2007,8(1):37-48
[13] Au CW, Siu MK, Liao X, et al. Tyrosine kinase B receptor and BDNF expressi-on in ovarian cancers-Effect on cell migration, angiogenesis and clinical out-come[J]. Cancer Lett.2009,281(2):151-61
[14] S. Burns,g.O. Cory, W. Vainchenker, et al. Mechanisms ofWASP-mediatedhaematological and immunological disease[J]. Blood.2004,104:3454–62
[15] A.gautreau,h.Y.ho, J. Li, et al. Purification and architecture of the ubiquito-usWAVE complex[J]. Proc. Natl. Acad. Sci. U. S. A.2004,101:4379–83
[16]周敏.应用反向捕获抗体芯片技术筛选子宫内膜异位症和上皮性卵巢癌血清自身抗体［D］.重庆：重庆医科大学，2011
[17] Kurisu S, Takenawa T.WASP and WAVE family proteins: friends or foes incancer invasion[J]? Cancer Sci.2010;101(10):2093-104.
[18] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regulation ofWAVE1-induced actin nucleation by Rac1and Nck[J].Nature.2002,418(6899):790-3
[19] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[20] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[21]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[22]康睿,曹励之,俞燕等. WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[1] Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010[J]. CA Cancer J Clin.2010,60(5):277-300
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J]. Rev Obstetgynecol.2011,4(1):15-21
[3]徐意瑶,卢欣,赵海涛等.卵巢癌肝转移的外科治疗[J].中华临床医师杂志（电子版）.2010,4(6):797-9
[4]崔恒.卵巢癌的诊治及其研究策略[J].中国妇产科临床杂志.2006,7(5):323-6
[5] Al Rawahi T, Lopes AD, Bristow RE, et al. Surgical cytoreduction for recurrentepithelial ovarian cancer[J]. Cochrane Database Syst Rev.2013, doi:10.1002/14651858.
[6] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011;15;71(2):349-59.
[7] Chambers SK, Clouser MC, Baker AF, Roe DJ,et al.Overexpression of tumorvascular endothelialgrowth factor A may portend an increased likelihood ofprogression in a phase II trial of bevacizumab and erlotinib in resistant ovariancancer[J].Clin Cancer Res.2010;1;16(21):5320-8.
[8] Lu L, Schwartz P, Scarampi L,et al. MicroRNA let-7a: a potential marker forselection of paclitaxel in ovarian cancer management[J].gynecol Oncol.2011,122(2):366-71.
[9] Noske A, Kaszubiak A, Weichert W, et al. Specific inhibition of AKT2by RNAinterference results in reduction of ovarian cancer cell proliferation: increasedexpression of AKT in advanced ovarian cancer[J].Cancer Lett.2007,246(1-2):190-200.
[10] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[11]周敏.应用反向捕获抗体芯片技术筛选子宫内膜异位症和上皮性卵巢癌血清自身抗体［D］.重庆：重庆医科大学，2011
[12] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes[J]. Wound RepairRegen.2010,18(6):594-604
[13] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008;18;582(14):2102-11.
[14] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[15] Sarmiento C, Wang W, Dovas A,et al. WASP family members and formin proteinscoordinate regulation of cell protrusions in carcinoma cells[J]. J Cell Biol.2008;24;180(6):1245-60.
[16]贺钰磊,曹励之,杨静等.急性淋巴细胞白血病患儿WAVE1和p22phox的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志.2009,11(2):88-92
[17]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[18] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[19] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved in theinvasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[20] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies[J]. Lancet.2007,369(9574):1742-57
[21] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[22]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[23] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[24] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[25] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008;180(4):1515-21
[26] Yang MH, Zhao MY,he YL, et al.Interaction of WAVE1andgenes involved inmultiple drug resistance in children with acute myeloblasticleukemia[J].Zhonghua Er Ke Za Zhi.2010;48(3):175-9
[27] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regμlation of WAVE1-induced actin nucleation by Rac1and Nck[J].Nature.2002,418(6899):790-3
[28] S. Burns,g.O. Cory, W. Vainchenker, et al. Mechanisms of WASP-mediatedha-ematological and immunological disease[J]. Blood.2004,104:3454–62
[29] A.gautreau,h.Y.ho, J. Li, et al. Purification and architecture of the ubiquito-usWAVE complex[J]. Proc. Natl. Acad. Sci. U. S. A.2004,101:4379–83
[30] Mikih, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involvedin actin reorganization induced by Rac[J]. EMBO J.1998,17(23):6932-41
[31] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement[J]. J Cell Sci.2001,114(10):1801-9
[32] Suetsugu S, Yamazaki D, Kurisu S, et al. Differential roles of WAVE1andWAVE2in dorsal and peripheral ruffle formation for fibroblast cell migration [J].Dev Cell.2003,5(4):595-609
[33] Suetsugu S, Mikih, Takenawa T. Identification of twohuman WAVE/SCAR-homologues asgeneral actin regulatory molecules which associate with the Arp2/3complex[J]. Biochem Biophys Res Commun.1999,260(1):296-302
[34] FernandohS, Davies SR, Chhabra A, et al. Expression of the WASP verprolin-homologues(WAVE members) inhuman breast cancer[J]. Oncology.2007,73(5-6):376-83
[35]贺钰磊,曹励之,杨明华等. WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[36] Yang LY, Tao YM, Ou DP, et al. Increased expression of Wiskott-Aldrichsyndrome protein family verprolin-homologous protein2correlated with poorprognosis ofhepatocellular carcinoma[J].Clin Cancer Res.2006,12(19):5673-9
[37] Iwaya K, Norio K, Mukai K. Coexpression of Arp2and WAVE2predicts pooroutcome in invasive breast carcinoma[J]. Mod Pathol.2007,20(3):339-43
[38] Chinni SR, Falchetto R,gercel-Taylor C, et al.humoral immune responses tocathepsin D andglucose-regulated protein78in ovarian cancer patients[J]. ClinCancer Res1997,3(9):1557–64.
[39] Korneeva I, Bongiovanni AM,girotra M, et al. Serum antibodies to the27-kdheatshock protein in women withgynecologic cancers[J]. Am J Obstetgyne-col2000,183(1):18–21.
[40] Tong YQ, Liu B, ZhenghY,et al. BMI-1autoantibody as a new potentialbiomarker for cervical carcinoma[J]. PLoS One.2011;6(11):e27804
[41] Chang W, Wu L, Cao F, et al. Development of autoantibody signatures asbiomarkers for early detection of colorectal carcinoma[J]. Clin Cancer Res.2011,17(17):5715-24
[42] Solassol J, Harmand PO, Maudelonde T, et al. Autoantibodies against tumor-related antigens: new tools for early detection of lung cancer[J]. Bull Cancer.2011,98(12):1419-30
[1] Castel SE, Martienssen RA. RNA interference in the nucleus: roles for smallRNAs in transcription, epigenetics and beyond[J]. Nat Revgenet.2013,14(2):100-12
[2] Lambeth LS, Smith CA. Short hairpin RNA-mediatedgene silencing[J]. MethodsMol Biol.2013,942:205-32
[3]陈湘琦,李志鹰,林挺岩. RNA干扰技术在肺癌基因治疗中的应用研究现状[J].中华临床医师杂志.2010,4(7):1028-31
[4]刘文康,王华,苍金荣等.特异性siRNA抑制宫颈癌细胞中iASPP基因的表达研究[J].现代检验医学杂志.2012,27(6):11-4
[5]宋清源生秀杰周冬梅等.RNA干扰沉默基质金属蛋白酶2基因对卵巢癌OVCAR-3细胞诱导体外血管形成能力的影响[J].肿瘤研究与临床.2012,12:793-6
[6] Wang C, Navab R, Iakovlev V, et al. Abelson interactor protein-1positivelyregulates breast cancer cell proliferation, migration, and invasion[J].Mol CancerRes.2007,5(10):1031-9
[7]段海霞,李东红,马向东.化学合成siRNA对卵巢癌SKOV3细胞中STA33基因表达的抑制作用[J].现代肿瘤医学.2012,20(8):1541-6
[8] Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutictarget for metastatic ovarian cancer[J].Cancer Res.2010,70(19):7570-9
[9] Wang J, Che YL, Lig, et al. Crk and CrkL present with different expression andsignificance in epithelial ovarian carcinoma[J].Mol Carcinog.2011,50(7):506-15
[10]林锐,张旭东.慢病毒介导的mcl-1-shRNA对食管癌细胞生长和化疗敏感性影响[J].临床与实验病理学杂志.2013,29(1):23-8
[11] Wangh, Linghuh, Wang J, et al. The role of Crk/Dock180/Rac1pathway in themalignant behavior ofhuman ovarian cancer cell SKOV3[J]. Tumour Biol.2010,31(1):59-67
[12] Chenh, Wu X, Pan ZK, et al. Integrity of SOS1/EPS8/ABI1tri-complexdetermines ovarian cancer metastasis[J]. Cancer Res.2010,70(23):9979-90
[13]丁明霞,李种,左毅刚等.人膀胱癌EJ细胞株CD44基因的小RNA干扰抑制细胞侵袭功能[J].现代泌尿生殖肿瘤杂志.2011,3(6):345-7
[14]贺钰磊,曹励之,杨明华等. WAVE1对K562细胞侵袭能力的影响及其机制研究.中华血液学杂志.2009,30(4):237-41
[15]陈国庆,姚珍薇,漆洪波等.慢病毒载体抑制FOXM1对卵巢癌SKOV3细胞增殖的影响与分子机制[J].细胞与分子免疫学杂志.2012,29-32
[16]王莉,李娜,吴小华.慢病毒介导的RNAi对卵巢癌细胞增殖及间皮素表达的影响[J].中国肿瘤生物治疗杂志.2008,15(2):134-8
[17] Couzin J. Breakthrough of the year. Small RNAs make big splash[J]. Science.2002,298(5602):2296-7
[18] Mroz EA, Rocco JW. RNA interference: natural, experimental, and clinical rolesin cancer biology[J].head Neck.2006,28(12):1132-41
[19] Preall JB, Sontheimer EJ. RNAi: RISCgets loaded. Cell.2005,123(4):543-5
[20] Filipowicz W. RNAi: the nuts and bolts of the RISC machine[J]. Cell.2005,122(1):17-20
[21] Napoli C, Lemieux C, Jorgensen R. Introduction of a Chimeric ChalconeSynthasegene into Petunia Results in Reversible Co-Suppression of homologous-genes in trans[J]. Plant Cell.1990,2(4):279-289
[22] Guo S, Kemphues KJ. par-1, agene required for establishing polarity in C.elegans embryos, encodes a putative Ser/Thr kinase that is asymmetricallydistributed[J]. Cell.1995,81(4):611-20
[23] Fire A, Xu S, Montgomery MK, et al. Potent and specificgenetic interference bydouble-stranded RNA in Caenorhabditis elegans. Nature[J].1998,391(6669):806-11
[24] Bots M, Maughan S, Nieuwland J. RNAi Nobel ignores vitalgroundwork onplants[J]. Nature.2006,443(7114):906
[25] Jorgensen R. Plants, RNAi, and the Nobel Prize[J]. Science.2006,314(5803):1242-3
[26] Shih, Wang J, Wang X, et al. Construction of eukaryotic expression vector ofshort hairpin RNA targetinghuman xylosyltransferase-Igene[J].hua Xi Kou QiangYi Xue Za Zhi.2008,26(2):206-10(in Chinese)
[27]段海霞,李东红,马向东.化学合成siRNA对卵巢癌SKOV3细胞中STA33基因表达的抑制作用[J].现代肿瘤医学.2012,20(8):1541-6
[28]史文天,王言奎,袁月秀等.化学合成siRNA沉默宫颈癌SiHa细胞E6基因表达的进一步研究[J].齐鲁医学杂志.2009,24(4):283-5
[29] Chen Y,huang L. Tumor-targeted delivery of siRNA by non-viral vector: safe andeffective cancer therapy[J]. Expert Opin Drug Deliv.2008,5(12):1301-11
[30] Martínez-Flores F, Jiménez-Orozco FA, Villegas-Castrejónh. Molecular biologyof adenoviral vectors[J]. Cir Cir.2006,74(6):483-93
[31] Witlox MA, Lamfersml, Wuisman PI, et al. Evolvinggene therapy approaches forosteosarcoma using viral vectors: review[J]. Bone.2007,40(4):797-812
[32] Frecha C, Szécsi J, Cosset FL, et al. Strategies for targeting lentiviral vectors[J].Currgene Ther.2008,8(6):449-60
[33] Schambach A, Baum C. Clinical application of lentiviral vectors-concepts andpractice[J]. Currgene Ther.2008,8(6):474-82
[34] Singer O, Verma IM. Applications of lentiviral vectors for shRNA delivery andtransgenesis[J]. Currgene Ther.2008,8(6):483-8
[35] Sumimotoh, Kawakami Y. Lentiviral vector-mediated RNAi and its use forcancer research[J]. Future Oncol.2007,3(6):655-64
[36] Ciuffi A. Mechanismsgoverning lentivirus integration site selection[J]. CurrgeneTher.2008,8(6):419-29
[37] Reynolds A, Leake D, Boese Q, et al. Rational siRNA design for RNAinterference[J]. Nat Biotechnol.2004,22(3):326-30
[38] Gong D, Ferrell JE Jr. Picking a winner: new mechanistic insights into the designof effective siRNAs[J]. Trends Biotechnol.2004,22(9):451-4
[39]康睿,曹励之,俞燕等. WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[40]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[41] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[42] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[1] Tang L, Yang J, Ng SK, et al. Autoantibody profiling to identify biomarkers ofkey pathogenic pathways in mucinous ovarian cancer[J]. European Journal ofCancer2010,46(1):170-179
[2] Rauh-Hain JA, Krivak TC, Del Carmenmg, et al. Ovarian cancer screening andearly detection in thegeneral population[J]. Rev Obstetgynecol.2011,4(1):15-21
[3] Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010[J]. CA Cancer J Clin.2010,60(5):277-300
[4] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[5] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility[J]. Annu Rev Cell Dev Biol.2005,21:695-18
[6]崔银江,李少华.E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[7]徐菊玲,邵圣文. Cdc42蛋白与细胞迁移、极化以及细胞骨架调节的关系[J].现代预防医学.2011,38(6):1148-9
[8] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[9] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis[J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[10] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia[J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[11] Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes incancer invasion?[J]. Cancer Sci.2010,101(10):2093-104
[12] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011;15;71(2):349-59.
[13] Chambers SK, Clouser MC, Baker AF, Roe DJ,et al.Overexpression of tumorvascular endothelialgrowth factor A may portend an increased likelihood ofprogression in a phase II trial of bevacizumab and erlotinib in resistant ovariancancer[J].Clin Cancer Res.2010;1;16(21):5320-8.
[14] Lu L, Schwartz P, Scarampi L,et al. MicroRNA let-7a: a potential marker forselection of paclitaxel in ovarian cancer management[J].Gynecol Oncol.2011,122(2):366-71.
[15]龙丽,唐良萏.绿茶提取物表没食子儿茶素3没食子酸酯对人卵巢癌HO-8910细胞增殖及信号通路相关基因表达的影响[J].中国生物制品学杂志.2012,25(9):1165-70
[16]范婷婷,唐良萏.NEK2基因沉默促进卵巢癌细胞SKOV3凋亡[J].基础医学与临床.2012,32(6):664-8.
[17] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion[J].Cancer Metastasis Rev.2009,28(1-2):15-33
[18] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[19]高卫栋,,王红兵,吴泽志等.肿瘤细胞迁移特性及细胞迁移能力表征[J].细胞生物学杂志.2008,30:451-6
[20] Vaňhara P,horak P, Pils D, et al. Loss of the oligosaccharyl transferase subunitTUSC3promotes proliferation and migration of ovarian cancer cells[J]. Int JOncol.2013,42(4):1383-9
[21] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes[J]. Wound RepairRegen.2010,18(6):594-604
[22] Heng JI, Chariot A, Nguyen L. Molecular layers underlying cytoskeletalremodeling during cortical development[J]. Trends Neurosci.2010,33(1):38-47
[23] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[24] Chi X, Wang S,huang Y, et al. Roles of rhogTPases in intracellular transport andcellular transformation[J]. Int J Mol Sci.2013,14(4):7089-108
[25] Oda A, Eto K. WASPs and WAVEs: From molecular function to physiologyinhematopoietic cells[J]. Semin Cell Dev Biol.2013,14. doi: S1084-9521(13)00029-3.
[26] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia[J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[27] Takahashi K, Suzuki K. WAVE2, N-WASP, and Mena facilitate cell invasion viaphosphatidylinositol3-kinase-dependent local accumulation of actin filaments[J]. J Cell Biochem.2011,112(11):3421-9
[28] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis[J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[29] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved inthe invasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[30]贺钰磊,曹励之,杨明华等.WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[31] Hale JS, Li M, Lathia JD.The malignant social network: cell-cell adhesion andcommunication in cancer stem cells[J].Cell Adh Migr.2012,6(4):346-55
[32] Lampugnanimg. Endothelial cell-to-cell junctions: adhesion and signaling inphysiology and pathology[J].Cold Springharb Perspect Med.2012,2(10).
[33] Carneiro P, Fernandes MS, Figueiredo J, et al. E-cadherin dysfunction ingastriccancer--cellular consequences, clinical applications and open questions[J]. FEBSLett.2012,586(18):2981-9
[34] Sampieri K, Fodde R. Cancer stem cells and metastasis[J]. Semin Cancer Biol.2012,22(3):187-93.
[35] Kohn EC,hurteau J.Ovarian cancer: making its own rules-again[J]. Cancer.2013,119(3):474-6
[36] Wu J, Liu Z, Shao C, et al.HMGA2overexpression-induced ovarian surfaceepithelial transformation is mediated through regulation of EMTgenes[J]. CancerRes.2011,71(2):349-59
[37] Zha L, Zhang J, Tang W, et al.HMGA2Elicits EMT by Activating theWnt/β-catenin Pathway ingastric Cancer[J]. Dig Dis Sci.2013,58(3):724-33
[38] Chen WC, Kuo TH, Tzeng YS, et al. Baicalin induces apoptosis in SW620humancolorectal carcinoma cells in vitro and suppresses tumorgrowth in vivo[J].Molecules.2012,17(4):3844-57
[39] Schou M, Brünner N, Spang-Thomsen M, et al. Mendelian analysis of ametastasis-prone substrain of BALB/c nude mice using a subcutaneouslyinoculatedhuman tumour[J]. APMIS.2006,114(12):899-907
[40] Brom M, Joosten L, Oyen WJ, et al. RadiolabelledgLP-1analogues for in vivotargeting of insulinomas[J]. Contrast Media Mol Imaging.2012,7(2):160-6
[1] Wade M, Li YC, WahlgM. MDM2, MDMX and p53in oncogenesis and cancertherapy[J]. Nat Rev Cancer.2013,13(2):83-96
[2] Muller PA, Vousden KH. p53mutations in cancer[J]. Nat Cell Biol.2013,15(1):2-8
[3]郭锐,雷小勇. miRNA靶位点SNP与肿瘤发生及其药物敏感性研究进展[J].中南医学科学杂志.2013,41(1):89-93
[4]杨光,裘正军.信号传导通路与肿瘤侵袭和转移机制的研究进展[J].现代肿瘤医学.2009,17(2):362-4
[5]张晔,刘云鹏.PI3K/Akt信号传导通路与肿瘤[J].中华临床医师杂志（电子版）.2010,10(20):96-9
[6]魏小勇,黎才海,饶荣生.p38MAPK信号通路与肿瘤的关系[J].实用癌症杂志.2009,24(1):101-3
[7] Kohn EC,hurteau J.Ovarian cancer: making its own rules-again[J]. Cancer.2013,119(3):474-6
[8] Leary A, Pautier P, Tazi Y, et al. The molecular biology of epithelial ovariancancer[J]. Bull Cancer.2012,99(12):1161-73
[9] Zhaoh, Yang Z, Wang X, et al. Triptolide inhibits ovarian cancer cell invasion byrepression of matrix metalloproteinase7and19and upregulation ofE-cadherin[J]. Exp Mol Med.2012,44(11):633-41
[10] Machesky LM. Lamellipodia and filopodia in metastasis and invasion[J]. FEBSLett.2008,582(14):2102-11
[11]崔银江,李少华. E-钙粘附素的研究进展[J].中国矫形外科杂志.2009,17(13):1001-3
[12] Canel M, Serrels A, Frame MC, et al. E-cadherin-integrin crosstalk in cancerinvasion and metastasis[J]. J Cell Sci.2013,126(Pt2):393-401
[13] Colas E, Pedrola N, Devis L, et al. The EMT signaling pathways in endometrialcarcinoma[J]. Clin Transl Oncol.2012,14(10):715-20
[14] Mell LK, Meyer JJ, Tretiakova M, et al.Prognostic significance of E-cadherinprotein expression in pathological stage I-III endometrial cancer[J]. Clin CancerRes.2004,10(16):5546-53
[15] Nagathihalli NS, Merchant NB. Src-mediated regulation of E-cadherin and EMTin pancreatic cancer[J]. Front Biosci.2012,17:2059-69
[16]徐洪涛,王恩华.E钙粘蛋白-环连蛋白复合体与肿瘤[J].国外医学：肿瘤学分册.2004,31(2):107-110
[17] Ba i B,hallerh, Mrkli I, et al. Prognostic role of E-cadherin in patients withadvanced serous ovarian cancer[J]. Archgynecol Obstet.2012, Epub ahead ofprint, PMID:23269354
[18] Ta kin S, Dünder I, Erol E, et al.Roles of E-cadherin and cyclooxygenaseenzymes in predicting different survival patterns of optimally cytoreduced serousovarian cancer patients[J]. Asian Pac J Cancer Prev.2012,13(11):5715-9
[19] PenghL,he L, Zhao X. Association of reduced immunohistochemical expressionof E-cadherin with a poor ovarian cancer prognosis--results of a meta-analysis[J].Asian Pac J Cancer Prev.2012,13(5):2003-7
[20] Knapinska A, FieldsgB. Chemical biology for understanding matrixmetalloproteinase function[J]. Chembiochem.2012,13(14):2002-20
[21] Bartlett JD, Smith CE. Modulation of cell-cell junctional complexes by matrixmetalloproteinases[J]. J Dent Res.2013,92(1):10-7
[22]董颖,赵长宏.基质金属蛋白酶与肿瘤侵袭转移的研究进展[J].实用肿瘤学杂志.2007,21(4):384-6
[23]孙春凤,黄国平,陈克平.基质金属蛋白酶-2的结构和功能[J].安徽医科大学学报.2013,48(3):330-2
[24] Rundhaug JE. Matrix metalloproteinases and angiogenesis[J]. J Cell Mol Med.2005,9(2):267-85
[25] Siefert SA, Sarkar R. Matrix metalloproteinases in vascular physiology anddisease Vascular[J].2012,20(4):210-6
[26] Lih,huang D,gao Z, et al. Scutellarin inhibits thegrowth and invasion ofhumantongue squamous carcinoma through the inhibition of matrix metalloproteinase-2and-9and αvβ6integrin[J]. Int J Oncol.2013,42(5):1674-81
[27] Laios A, Mohamed BM, Kelly L, et al. Pre-Treatment of Platinum ResistantOvarian Cancer Cells with an MMP-9/MMP-2Inhibitor Prior to CisplatinEnhances Cytotoxicity as Determined byhigh Content Screening[J]. Int J Mol Sci.2013,14(1):2085-103
[28] Hu X, Li D, Zhang W, et al. Matrix metalloproteinase-9expression correlateswith prognosis and involved in ovarian cancer cell invasion[J]. ArchgynecolObstet.2012,286(6):1537-43
[29] Noh S, Jung JJ, Jung M, et al. Body fluid MMP-2as a putative biomarker inmetastatic breast cancer[J]. Oncol Lett.2012,3(3):699-703
[30] Puljiz M, Puljiz Z, Vucemilo T, et al. Prognostic significance of matrixmetalloproteinases2and9in endometrial cancer. Coll Antropol[J].2012,36(4):1367-72
[31]王前,邓晶,蒋永新. cyclin D1的研究进展[J].现代肿瘤医学.2009,17(2):350-3
[32]贾文娟,李胜泽.STAT3、cyclin D1在妇科肿瘤中的研究进展[J].蚌埠医学院学报.2009,34(2):182-4
[33]王福生.周期素D1与肿瘤研究进展[J].国外医学：临床生物化学与检验学分册.2000,21(3):140-1
[34] Li N, Zhong X, Lin X, et al. Lin-28homologue A (LIN28A) promotes cell cycleprogression via regulation of cyclin-dependent kinase2(CDK2), cyclin D1(CCND1), and cell division cycle25homolog A (CDC25A) expression incancer[J]. J Biol Chem.2012,287(21):17386-97
[35] Ashrafi M, Bathaie SZ, Abroun S.high Expression of Cyclin D1and p21inN-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats[J]. Cell J.2012,14(3):193-202
[36] Lin S, YuhS. Clinical significance of nucleostemin expression and its correlationwith cyclin D1expression in malignant ovarian tumors[J]. Int Jgynecol Cancer.2011,21(7):1166-71
[37]田冬艳,王德华,刘永红. Survivin和Cyclin D1在卵巢癌中的表达和相关性[J].天津医科大学学报.2009,15(1):81-3
[38]Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors inregulation of angiogenesis and lymphangiogenesis[J]. Exp. Cell. Res.2006,312(5):549-60
[39]Takahashih, Shibuya, M. The vascular endothelialgrowth factor (VEGF)/VEGFreceptor system and its role under physiological and pathological conditions[J].Clin Sci.2005,109(3),227～241.
[40] Yu L, Deng L, Li J, et al. The prognostic value of vascular endothelialgrowthfactor in ovarian cancer: a systematic review and meta-analysis[J].gynecol Oncol.2013,128(2):391-6
[41]李慧玲,苏亚娟,邬剑等.MMP-2、VEGF在卵巢癌组织中的表达及其临床意义[J].中国实验诊断学.2009,13(6):726-9
[41]曾晓林,彭耀金. VEGF、MMP-2与MMP-9在卵巢癌组织中的表达及其临床意义[J].现代生物医学进展.2010,10(12):2322-4
[42]蔡冬燕,韩凤娟,闫忠鑫等.VEGF表达与卵巢癌相关性的研究进展[J].世界中西医结合杂志.2012,7(12):1091-3
[43]张洪英,陈军宝,卢宏柱.PI3K/Akt信号通路在肿瘤血管形成中的作用研究进展[J].山东医药.2012,52(47):98-100
[44]胡蕾,姜汉国.PI3K／AKT信号传导通路与肿瘤转移及其机制的研究进展[J].医学综述.2006,12(22):1375-7
[45]徐林林,梅金红.丝裂原活化蛋白激酶信号通路与卵巢癌关系的研究进展[J].实用癌症杂志.2007,22(5):540-2
[46] Zhu C, Qi X, Chen Y, et al. PI3K/Akt and MAPK/ERK1/2signaling pathways areinvolved in IGF-1-induced VEGF-C upregulation in breast cancer[J]. J CancerRes Clin Oncol.2011,137(11):1587-94
[47] Chang MC, Chen CA, Chen PJ, et al. Mesothelin enhances invasion of ovariancancer by inducing MMP-7through MAPK/ERK and JNK pathways[J]. BiochemJ.2012,442(2):293-302.
[48] Chang MC, Chen CA, Chen PJ, Chiang YC, Chen YL, Mao TL, et al. Oppositeregulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression,cell-associated procoagulant activity and invasiveness in MDA-MB-231cells [J].Jhematol Oncol.2012,5(1):16.
[49] Reuben PM, CheunghS. Regulation of matrix metalloproteinase (MMP)geneexpression by protein kinases[J]. Front Biosci.2006,11:1199-215
[50] Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediatesinsulin-likegrowth factor1-induced E-cadherin down-regulation and cellproliferation in ovarian cancer cells[J]. Cancer Lett.2012,326(2):191-8.
[1] Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatmentstrategies [J]. Lancet.2007,369(9574):1742-57
[2] Condeelis J, Singer RH, Segall JE. Thegreat escape: when cancer cellshijackthegenes for chemotaxis and motility [J]. Annu Rev Cell Dev Biol.2005,21:695-18
[3] Machesky LM. Lamellipodia and filopodia in metastasis and invasion [J]. FEBSLett.2008,582(14):2102-11
[4] Yilmaz M, Christoforig. EMT, the cytoskeleton, and cancer cell invasion [J].Cancer Metastasis Rev.2009,28(1-2):15-33
[5]崔银江,李少华. E-钙粘附素的研究进展.中国矫形外科杂志.2009,17(13):1001-3
[6] Kedrin D, van Rheenen J,hernandez L, et al. Cell motility and cytoskeletalregulation in invasion and metastasis [J]. J Mammarygland Biol Neoplasia.2007,12(2-3):143-52
[7] Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility [J]. Clin ExpMetastasis.2009,26(4):273-87
[8]高卫栋,王红兵,吴泽志等.肿瘤细胞迁移特性及细胞迁移能力表征[J].细胞生物学杂志.2008,30(4):451-6
[9] Vaňhara P,horak P, Pils D, et al. Loss of the oligosaccharyl transferase subunitTUSC3promotes proliferation and migration of ovarian cancer cells [J]. Int JOncol.2013,42(4):1383-9
[10] Jiang WG, Ye L, Patelg, et al. Expression of WAVEs, the WASP (Wiskott-Aldrichsyndrome protein) family of verprolinhomologous proteins inhuman woundtissues and the biological influence onhuman keratinocytes [J]. Wound RepairRegen.2010,18(6):594-604
[11] Yamaguchih, Condeelis J. Regulation of the actin cytoskeleton in cancer cellmigration and invasion[J]. Biochim Biophys Acta.2007,1773(5):642-52
[12]周方正,伍钢.细胞伪足与肿瘤转移研究进展[J].临床肿瘤学杂志.2007,12(1):77-9
[13] Heng JI, Chariot A, Nguyen L. Molecular layers underlying cytoskeletalremodeling during cortical development [J]. Trends Neurosci.2010,33(1):38-47
[14] Stradal TE, Rottner K, Disanza A, et al. Regulation of actin dynamics by WASPand WAVE family protein [J]. Trends Cell Biol.2004,14(6):303-11
[15] Chi X, Wang S,huang Y, et al. Roles of rhogTPases in intracellμlar transport andcellμlar transformation [J]. Int J Mol Sci.2013,14(4):7089-108
[16] Oda A, Eto K. WASPs and WAVEs: From molecμlar function to physiologyinhematopoietic cells [J]. Semin Cell Dev Biol.2013,14. doi: S1084-9521(13)00029-3.
[17] Patel FB, Soto MC. WAVE/SCAR promotes endocytosis and early endosomemorphology in polarized C. elegans epithelia [J]. Dev Biol.2013, doi:10.1016/j.ydbio.2013.03.012
[18] Takahashi K, Suzuki K. WAVE2, N-WASP, and Mena facilitate cell invasion viaphosphatidylinositol3-kinase-dependent local accumulation of actin filaments[J]. J Cell Biochem.2011,112(11):3421-9
[19] Sossey-Alaoui K. Surfing the big WAVE: Insights into the role of WAVE3as adriving force in cancer progression and metastasis [J]. Semin Cell Dev Biol.2012, doi:10.1016/j.semcdb.2012.10.006
[20] Massaad MJ, Ramesh N,geha RS. Wiskott-Aldrich syndrome: a comprehensivereview[J]. Ann N Y Acad Sci.2013,. doi:10.1111/nyas.12049.
[21] Notarangelo LD, Miao CH, OchshD, et a1. Wiskott-Aldrich syndrome [J]．CurrOpinhematol,2008,15(1):30-6
[22] Derry JM, OchshD, Francke U: Isolation of a novelgene mutated inWiskott-Aldrich syndrome [J]. Cell.1994,78(4):635-44.
[23] Mikih, Miura K, Takenawa T. N-WASP, a novel actin-depolymerizing protein,regulates the cortical cytoskeletal rearrangement in a PIP2-dependent mannerdownstream of tyrosine kinases[J]. EMBO J.1996,15(19):5326-35
[24] Mikih, Suetsugu S, Takenawa T. WAVE, a novel WASP-family protein involvedin actin reorganization induced by Rac[J]. EMBO J.1998,17(23):6932-41
[25] Suetsugu S, Mikih, Takenawa T. Identification of twohuman WAVE/SCAR-homologues asgeneral actin regulatory molecules which associate with theArp2/3complex[J]. Biochem Biophys Res Commun.1999,260(1):296-302
[26]张利军,魏蕾. WAVE2与细胞骨架的研究进展[J].武汉大学学报：医学版.2005,26(5):678-682
[27] Takenawa T, Mikih. WASP and WAVE family proteins: key molecules for rapidrearrangement of cortical actin filaments and cell movement[J]. J Cell Sci.2001,114(10):1801-9
[28] Vartiainen MK, Machesky LM. The WASP-Arp2/3pathway:genetic insights[J].Curr Opin Cell Biol.2004,16(2):174-81
[29] Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting themembrane to the cytoskeleton[J]. Nat Rev Mol Cell Biol.2007,8(1):37-48
[30] Rohatgi R,hohY, Kirschner MW. Mechanism of N-WASP activation by CDC42and phosphatidylinositol4,5-bisphosphate[J]. J Cell Biol.2000,150(6):1299-310
[31] Mikih, Yamaguchih, Suetsugu S, et a1. IRSp53is an essential intermediatebetween Rac and WAVE in the regulation of membrane ruffling[J]. Nature.2000,408(6813):732-5
[32] Soderling SH, Binns KL, WaymangA, et al. The WRP component of the WAVE-1complex attenuates Rac-mediated signalling[J]. Nat Cell Biol.2002,4(12):970-5
[33] Gautreau A,hohY, Li J, et al. Purification and architecture of the ubiquitous Wavecomplex[J]. Proc Natl Acad Sci U S A.2004,101(13):4379-83
[34] Echarri A, Lai MJ, Robinson MR, et al. Abl interactor1(Abi-1) wave-bindingand SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodiumlocalization, and wave-1levels[J]. Mol Cell Biol.2004,24(11):4979-93
[35] Innocenti M,gerboth S, Rottner K, et al. Abi1regulates the activity of N-WASPand WAVE in distinct actin-based processes[J]. Nat Cell Biol.2005,7(10):969-76
[36] Mikih, Takenawa T. WAVE2serves a functional partner of IRSp53by regulatingits interaction with Rac[J]. Biochem Biophys Res Commun.2002,293(1):93-9
[37] Beltzner CC, Pollard TD. Pathway of actin filament branch formation by Arp2/3complex[J]. J Biol Chem.2008,283(11):7135-44
[38] Sirotkin V, Beltzner CC, Marchand JB, et al. Interactions of WASp, myosin-1,and verprolin with Arp2/3complex during actin patch assembly in fission yeast[J]. J Cell Biol.2005,170(4):637-48
[39] Pollard TD, Beltzner CC. Structure and function of the Arp2/3complex[J]. CurrOpin Struct Biol.2002,12(6):768-74
[40] Pollard TD, BorisygG. Cellular motility driven by assembly and disassembly ofactin filaments [J]. Cell,2003,113(4):453-65
[41] Richardson BE, BeckeR K, Scott J, et a1. SCAR/WAVE and Arp2/3are crucialfor cytoskeletal remodeling at the site of myoblast fusion [J]. Development.2007,134(24):4357-67
[42] Yamaguchih, Mikih, Suetsugu S, et al. Two tandem verprolinhomology domainsare necessary for a strong activation of Arp2/3complex-induced actinpolymerization and induction of microspike formation by N-WASP[J]. Proc NatlAcad Sci U S A.2000,97(23):12631-6
[43] de la Fuente MA, Sasahara Y, Calamito M, et al. WIP is a chaperone forWiskott-Aldrich syndrome protein (WASP)[J]. Proc Natl Acad Sci U S A.2007,104(3):926-31
[44] HohY, Rohatgi R, Lebensohn AM, et al. Toca-1mediates Cdc42-dependent actinnucleation by activating the N-WASP-WIP complex[J]. Cell.2004,118(2):203-16
[45] Suetsugu S, Banzai Y, Kato M, et al. Male-specific sterility caused by the loss ofCR16.genes Cells.2007,12(6):721-33
[46] Sawa M, Takenawa T. Caenorhabditis elegans WASP-interacting proteinhomologue WIP-1is involved in morphogenesis through maintenance of WSP-1protein levels[J]. Biochem Biophys Res Commun.2006,340(2):709-17
[47] Volkman BF, Prehoda KE, Scott JA, et al. Structure of the N-WASP EVH1domain-WIP complex: insight into the molecular basis of Wiskott-AldrichSyndrome[J]. Cell.2002,111(4):565-76
[48] Imai K, Nonoyama S, OchshD. WASP (Wiskott-Aldrich syndrome protein)genemutations and phenotype[J]. Curr Opin Allergy Clin Immunol.2003,3(6):427-36
[49] Symons M, Derry JM, Karlak B, et al. Wiskott-Aldrich syndrome protein, a noveleffector for thegTPase CDC42Hs, is implicated in actin polymerization[J]. Cell.1996,84(5):723-34
[50] Kurisu S, Takenawa T. The WASP and WAVE family proteins.genome Biol[J].2009,10(6):226
[51] Innocenti M, Zucconi A, Disanza A, et al. Abi1is essential for the formation andactivation of a WAVE2signalling complex[J]. Nat Cell Biol.2004,6(4):319-27
[52] Eden S, Rohatgi R, Podtelejnikov AV, et al. Mechanism of regulation ofWAVE1-induced actin nucleation by Rac1and Nck Nature[J].2002,418(6899):790-3
[53] Jenei V, Andersson T, Jakus J, et al. E3B1, ahumanhomologue of the mousegeneproduct Abi-1, sensitizes activation of Rap1in response to epidermalgrowthfactor[J]. Exp Cell Res.2005,310(2):463-73
[54] Suetsugu S, Mikih, Yamaguchih, et al. Enhancement of branching efficiency bythe actin filament-binding activity of N-WASP/WAVE2[J]. J Cell Sci.2001,114(24):4533-42
[55] Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes incancer invasion?[J]. Cancer Sci.2010,101(10):2093-104
[56] Kim AS, Kakalis LT, Abdul-Manan N, et al. Autoinhibition and activationmechanisms of the Wiskott-Aldrich syndrome protein. Nature[J].2000,404(6774):151-8
[57] Prehoda KE, Scott JA, Mullins RD, et al. Integration of multiple signals throughcooperative regulation of the N-WASP-Arp2/3complex[J]. Science.2000,290(5492):801-6
[58] Suetsugu S,hattori M, Mikih, et al. Sustained activation of N-WASP throughphosphorylation is essential for neurite extension[J]. Dev Cell.2002,3(5):645-58
[59] CorygO,garg R, Cramer R,et al. Phosphorylation of tyrosine291enhances theability of WASp to stimulate actin polymerization and filopodium formation.Wiskott-Aldrich Syndrome protein[J]. J Biol Chem.2002,277(47):45115-21
[60] CorygO, Cramer R, Blanchoin L, et al. Phosphorylation of the WASP-VCAdomain increases its affinity for the Arp2/3complex and enhances actinpolymerization by WASP[J]. Mol Cell.2003,11(5):1229-39
[61] Park SJ, Suetsugu S, Takenawa T. Interaction ofhSP90to N-WASP leads toactivation and protection from proteasome-dependent degradation[J]. EMBO J.2005,24(8):1557-70
[62] Cestrag, Toomre D, Chang S, et al. The Abl/Arg substrate ArgBP2/nArgBP2coordinates the function of multiple regulatory mechanisms converging on theactin cytoskeleton[J]. Proc Natl Acad Sci U S A.2005,102(5):1731-6
[63] Rogers SL, Wiedemann U, Stuurman N, et al. Molecular requirements foractin-based lamella formation in Drosophila S2cells[J]. J Cell Biol.2003,162(6):1079-88.
[64]崔梅花,郁卫东. Abl相互作用蛋白-1在肿瘤基础与临床研究中的进展[J].中国现代医学杂志.2011,21(17):2021-5
[65] Steffen A, Rottner K, Ehinger J, et al. Sra-1and Nap1link Rac to actin assemblydriving lamellipodia formation[J]. EMBO J.2004,23(4):749-59
[66] Leng Y, Zhang J, Badour K, et al. Abelson-interactor-1promotes WAVE2membrane translocation and Abelson-mediated tyrosine phosphorylation requiredfor WAVE2activation[J]. Proc Natl Acad Sci U S A.2005,102(4):1098-103
[67]张秀真,吴泽志.细胞伪足形成与微丝骨架研究进展[J].国外医学：临床生物化学与检验学分册.2005,26(4):213-6
[68] Baldassarre M, Pompeo A, Beznoussenkog, et al. Dynamin participates in focalextracellular matrix degradation by invasive cells[J]. Mol Biol Cell.2003,14(3):1074-84
[69] Buccione R, Orth JD, McNiven MA. Foot and mouth: podosomes, invadopodiaand circular dorsal ruffles[J]. Nat Rev Mol Cell Biol.2004,5(8):647-57
[70] Chuang YY, Tran NL, Rusk N, et al. Role of synaptojanin2inglioma cellmigration and invasion[J]. Cancer Res.2004,64(22):8271-5
[71] Linder S, Aepfelbacher M. Podosomes: adhesionhot-spots of invasive cells[J].Trends Cell Biol.2003,13(7):376-85
[72] Linder S, Nelson D, Weiss M, et al. Wiskott-Aldrich syndrome protein regulatespodosomes in primaryhuman macrophages[J]. Proc Natl Acad Sci U S A.1999,96(17):9648-53
[73] Yamaguchih, Lorenz M, Kempiak S, et al. Molecular mechanisms ofinvadopodium formation: the role of the N-WASP-Arp2/3complex pathway andcofilin[J]. J Cell Biol.2005,168(3):441-52
[74] Raftopoulou M,hall A. Cell migration: RhogTPases lead the way[J]. Dev Biol.2004,265(1):23-32
[75] Suetsugu S, Yamazaki D, Kurisu S, et al. Differential roles of WAVE1andWAVE2in dorsal and peripheral ruffle formation for fibroblast cell migration[J].Dev Cell.2003,5(4):595-609
[76] Yamazaki D, Fujiwara T, Suetsugu S, et al. A novel function of WAVE inlamellipodia: WAVE1is required for stabilization of lamellipodial protrusionsduring cell spreading[J]. genes Cells.2005,10(5):381-92
[77] Takenawa T. From N-WASP to WAVE: key molecules for regulation of corticalactin organization[J]. Novartis Found Symp.2005,269:3-10
[78] Kurisu S, Suetsugu S, Yamazaki D, et al. Rac-WAVE2signaling is involved in theinvasive and metastatic phenotypes of murine melanoma cells[J]. Oncogene.2005,24(8):1309-19
[79] Sossey-Alaoui K, Ranalli TA, Li X, et al. WAVE3promotes cell motility andinvasion through the regulation of MMP-1, MMP-3, and MMP-9expression[J].Exp Cell Res.2005,308(1):135-45
[80] Yang LY, Tao YM, Ou DP, et al. Increased expression of Wiskott-Aldrichsyndrome protein family verprolin-homologous protein2correlated with poorprognosis ofhepatocellular carcinoma[J]. Clin Cancer Res.2006,12(19):5673-9
[81] FernandohS, Sanders AJ, KynastonhG, et al. WAVE1is associated withinvasiveness andgrowth of prostate cancer cells[J]. J Urol.2008,180(4):1515-21
[82] FernandohS, Sanders AJ, KynastonhG, et al. WAVE3is associated withinvasiveness in prostate cancer cells[J]. Urol Oncol.2010,28(3):320-7
[83] Cai X, Xiao T, James SY, et al. Metastatic potential of lung squamous cellcarcinoma associated withhSPC300through its interaction with WAVE2[J]. LungCancer.2009,65(3):299-305
[84] Semba S, Iwaya K, Matsubayashi J, et al. Coexpression of actin-related protein2and Wiskott-Aldrich syndrome family verproline-homologous protein2inadenocarcinoma of the lung[J]. Clin Cancer Res.2006,12(8):2449-54
[85]康睿,曹励之,俞燕等. WAVE1基因在K562／A02白血病细胞多药耐药中的作用[J].中华血液学杂志.2007,28(6):379-82
[86]王卓,胡婷,曹励之等.儿童急性淋巴细胞白血病及阿霉素所致Jurkat细胞凋亡时WAVE1表达研究[J].中国当代儿科杂志.2008,10(5):620-4
[87]贺钰磊,曹励之,杨明华等.WAVE1对K562细胞侵袭能力的影响及其机制研究[J].中华血液学杂志.2009,30(4):237-41
[88]贺钰磊,曹励之,杨静等.急性淋巴细胞白血病患儿WAVE1和p22phox的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志.2009,11(2):88-92
[89]杨明华,赵明一,贺钰磊等.儿童急性髓细胞性白血病WAVE1基因对耐药相关基因表达影响的研究[J].中华儿科杂志.2010,48(3):175-9
[90]1waya K, Oikawa K, Semba S, et a1. Correlation between liver metastasis of thecolocalization of actin-related protein2and3complex and WAVE2in colorectalcarcinoma[J].Cancer Sci.2007,98(7):992-9
[91] FernandohS, Davies SR, Chhabra A, et al. Expression of the WASPverprolin-homologues (WAVE members) inhuman breast cancer[J]. Oncology.2007,73(5-6):376-83
[92] Iwaya K, Norio K, Mukai K. Coexpression of Arp2and WAVE2predicts pooroutcome in invasive breast carcinoma[J]. Mod Pathol.2007,20(3):339-43
[93] Sossey-Alaoui K, Safina A, Li X, et al. Down-regulation of WAVE3, a metastasispromotergene, inhibits invasion and metastasis of breast cancer cells[J]. Am JPathol.2007,170(6):2112-21
[94] Martin TA, Pereirag, Watkinsg, et al. N-WASP is a putative tumour suppressor inbreast cancer cells, in vitro and in vivo, and is associated with clinical outcome inpatients with breast cancer[J]. Clin Exp Metastasis.2008,25(2):97-108
[95]黄琰菁,于世英,王江玲等.乳腺癌中Abi1和c-Abl及WAVE2的表达及其相互关系[J].中国组织化学与细胞化学杂志.2010,19(3):216-20