mTOR信号通路和survivin在人脑神经胶质瘤中的表达及临床意义
摘要
研究背景：
人脑神经胶质瘤(human gliomas)是中枢神经系统中最为常见的一种原发性恶性肿瘤,在临床中其发病具有“三高一低”的特点,即高发病、高复发、高死亡和低治愈。根据神经胶质瘤的恶性程度一般可以大致分为低分级胶质瘤(low-grade glioma, LGG)和高分级胶质瘤(High-grade glioma, HGG)。治疗中一般采用以手术切除肿瘤组织为主要治疗方案,但是由于胶质瘤通常呈侵润性生长,与正常脑组织粘连以致分界不清,术中难以完全切除,因而在手术后常常要辅助于化疗、放疗等综合治疗。即便如此,神经胶质瘤恶性的生物学特征决定了术后复发常常难以避免。因此,对胶质瘤发病机制进行深入研究,有望提高对神经胶质瘤的诊治水平,改善患者生活质量,延长患者的生存期。
研究目的：
神经胶质瘤的发病机制一般认为和多个调控基因异常过度表达或者受到抑制有关。而哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是一种非典型丝氨酸/苏氨酸蛋白激酶,与此同时,它也是一类重要的信号通路转导分子,在基因表达及细胞增殖中发挥中间桥梁作用。Survivin又称存活蛋白,是凋亡抑制蛋白家族之一,Survivin通常只表达于恶性肿瘤或者某些胚胎组织,在正常组织中表达甚少,因而具有较好的特异性,而且其表达情况多和肿瘤细胞的增殖及浸润转移有密切的关系。本研究通过免疫组化检测71例胶质瘤中mTOR及survivin的表达,并进行差异性和相关性统计分析,从而探讨其在人脑胶质瘤中的表达及其相互关系,为临床诊断与治疗提供一定的帮助。
材料和方法：
本实验的收集了2010年11月-2012年10月期间郑州大学第一附属医院神经外科71例神经胶质瘤患者的术中切除的神经胶质瘤组织及临床资料,根据病理检测的结果,把神经胶质瘤标本病理级别分为Ⅰ级16例,Ⅱ级19例,Ⅲ级17例,Ⅳ级19例。其中把Ⅰ、Ⅱ级神经胶质瘤标本合并为低分级组,把Ⅲ、Ⅳ级神经胶质瘤标本合并为高分级组,另外再取10例脑外伤行减压术的患者的正常脑组织作为对照组。采用半定量免疫组化(Envision法)检测mTOR和survivin的表达强度,最后用χ2检验及Spearman相关性来分析研究mTOR和survivin在各个病理级别神经胶质瘤中的阳性表达情况,再以Spearman秩相关来分析mTOR与suivivin的相关性,探讨它们之间的生物性联系。
研究结果：
mTOR和survivin均定位于细胞核或者细胞浆,在肿瘤中呈现弥漫状分布,以在细胞内出现淡黄、棕褐色颗粒为阳性表达。mTOR在神经胶质瘤中的阳性率分别为低级别Ⅰ-Ⅱ级为37.14%(13/35),高级别Ⅲ-Ⅳ级为69.44%(25/36)；survivin的阳性表达率为低级别Ⅰ-Ⅱ级40.00%(14/35),高级别Ⅲ-Ⅳ级66.67%(24/36)；而mTOR和survivin在正常脑组织中均未见表达。根据χ2检验统计结果示,mTOR和survivin在高级别脑神经胶质瘤中的表达明显高于低级别胶质瘤,其差异具有统计学意义(P<0.01)),根据Spearman相关性检验,mTOR和survivin的表达强度均随着胶质瘤病理级别的升高而增加,其差异均具有统计学意义(rmTOR=0.470, P<0.01; rsurvivin=0.399, P<0.05); mTOR与survivin在人脑神经胶质瘤中的表达呈现相关性(rs=0.264,P=0.026<0.05)。
研究结论：
mTOR信号通路和人脑神经胶质瘤的恶性程度相关,随着神经胶质瘤病理级别的升高而表达增加；Survivin的表达在在神经胶质瘤中亦随着神经胶质瘤的病理级别的升高而表达增加,并且mTOR和survivin的表达具有一定的相关性,两者在神经胶质瘤的产生中有重要意义。因而可以推测mTOR和survivin可能在神经胶质瘤的发生发展中具有重要的作用。临床上可以考虑给予相应的单一或者联合靶向治疗,以期促进治疗方案及效果的提高。
Background
Human gliomas are one of the most common intracranial primary malignant tumors of the central nervous system.The incidence has the characteristic of "three high and one low",namely, which means the high incidence、the high mortality、the high recurrence and the low cure rate.According to the degree of malignancy,gliomas are generally divided into low grade gliomas (low-grade glioma, LGG) and high grade glioma (High-grade glioma, HGG).Grade Ⅲ、Ⅳ gliomas are regarded as malignant gliomas by the classification standard of WHO (2000).Nowadays,the treatment of operation is the main remedial method.But because of gliomas are usually invasive growth,the division with normal brain tissue is commonly not clear,It is very difficult to cut off the gliomas completely.Thus the postoperative treatment often need the combined chemotherapy or radiotherapy.Even so,the biological characteristics of gliomas often decide that it is impossible to avoid the recurrence of gliomas.Therefore,in-depth study of the pathogenesis of glioma can improve the level of diagnosis and treatment,prolong the survival time of patients.And the recurrence factors of glioma were analyzed to explore the appropriate treatment measures,which may have reduced brain gliomas recurrence rate,improve the quality of life of patients,and has certain social significance and economic value.
Objective
The etiology of human gliomas are connected with a plurality of abnormal gene expression or inhibition.The mammalian target of rapamycin (mammalian target of rapamycin,mTOR) is an atypical serine/threonine protein kinase, which is also an important signal transduction molecule. Survivin is one of the inhibitor of apoptosis protein family, which is usually only expressed in tumor or some embryonic organization. Survivin has a good specificity, and has the relationship with tumor cell proliferation and invasion metastasis. This purpose of the experiment is to determine the expression level of mTOR and survivin in glioma tissues of human brain, and to analyze the relationship of mTOR with the malignancy and prognosis of gliomas
Materials and Methods
In the study,gliomas tissues from71patients (40males and31females,average age of44.09±12.06years,rang11±68age), which were prospectively collected from the neurosurgery the of the first affiliated hospital of Zhengzhou university,According to the pathological examination,the pathological grade of glioma specimens of7cases were in grade I,14cases of grade11,22cases in grade Ⅲ,28cases of grade IV.Grade I and II of the glioma are combined to low grade group.Grade III and IV of the glioma are combined to high grade group,.Another10cases normal brain tissue of patients who were underwent the decompression as the result of the brain traumas as control group.The semi-quantitative immunohistochemistry (Envision method) were used to detect the expression intensity of mTOR and survivin.Finally,χ2test and Fisher exact were considered the appropriate methods to calculate the difference between normal brain tissue and low grade malignancy group, low grade malignancy group and high grade malignancy group.Furthermore,Spearman rank correlation analysis were used to analyze the correlation between mTOR and survivin.
Results
mTOR and Survivin were located in the nucleus or cytoplasm,which showed diffuse distribution and yellow,brown granulesin for positive expression in tumor cells.The positive rate of grade I and II of mTOR in all glioma were37.14%(13/35) and the positive rate of grade III and IV of mTOR were69.44%(25/36) of grade III and IV.The positive rate of grade I and II of survivin in all glioma were40.00%(14/35) and the positive rate of grade III and IV of survivin were66.67%(24/36) of grade III and IV.While the mTOR and Survivin in normal brain tissue had no expression.According to the statistical results of x2test and Fisher exact probability, the expression of mTOR in glioma are significantly higher than that in low grade gliomas,the difference was statistically significant (P<0.01)),the intensity of survivin expression increased with the malignant degree of glioma and the significantly. the difference was statistically significant (P<0.01).
Conclusions
The malignant degree of mTOR signal pathway have the relation with the expression of human gliomas.The expression magnitude of the mTOR in high grade gliomas than in low grade gliomas.The expression magnitude of survivin in glioma malignant also increased with the increased grade malignancy of gliomas.According to the research,mTOR and Survivin have the correlation,which also have important significance in glioma.Thus,it can be inferred that mTOR and Survivin may have the important role in the development of. gliomas. the corresponding single or combination of targeted therapy can be considered to give in clinical in order to promote and improve the effect of treatment.
人脑神经胶质瘤(human gliomas)是中枢神经系统中最为常见的一种原发性恶性肿瘤,在临床中其发病具有“三高一低”的特点,即高发病、高复发、高死亡和低治愈。根据神经胶质瘤的恶性程度一般可以大致分为低分级胶质瘤(low-grade glioma, LGG)和高分级胶质瘤(High-grade glioma, HGG)。治疗中一般采用以手术切除肿瘤组织为主要治疗方案,但是由于胶质瘤通常呈侵润性生长,与正常脑组织粘连以致分界不清,术中难以完全切除,因而在手术后常常要辅助于化疗、放疗等综合治疗。即便如此,神经胶质瘤恶性的生物学特征决定了术后复发常常难以避免。因此,对胶质瘤发病机制进行深入研究,有望提高对神经胶质瘤的诊治水平,改善患者生活质量,延长患者的生存期。
研究目的：
神经胶质瘤的发病机制一般认为和多个调控基因异常过度表达或者受到抑制有关。而哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是一种非典型丝氨酸/苏氨酸蛋白激酶,与此同时,它也是一类重要的信号通路转导分子,在基因表达及细胞增殖中发挥中间桥梁作用。Survivin又称存活蛋白,是凋亡抑制蛋白家族之一,Survivin通常只表达于恶性肿瘤或者某些胚胎组织,在正常组织中表达甚少,因而具有较好的特异性,而且其表达情况多和肿瘤细胞的增殖及浸润转移有密切的关系。本研究通过免疫组化检测71例胶质瘤中mTOR及survivin的表达,并进行差异性和相关性统计分析,从而探讨其在人脑胶质瘤中的表达及其相互关系,为临床诊断与治疗提供一定的帮助。
材料和方法：
本实验的收集了2010年11月-2012年10月期间郑州大学第一附属医院神经外科71例神经胶质瘤患者的术中切除的神经胶质瘤组织及临床资料,根据病理检测的结果,把神经胶质瘤标本病理级别分为Ⅰ级16例,Ⅱ级19例,Ⅲ级17例,Ⅳ级19例。其中把Ⅰ、Ⅱ级神经胶质瘤标本合并为低分级组,把Ⅲ、Ⅳ级神经胶质瘤标本合并为高分级组,另外再取10例脑外伤行减压术的患者的正常脑组织作为对照组。采用半定量免疫组化(Envision法)检测mTOR和survivin的表达强度,最后用χ2检验及Spearman相关性来分析研究mTOR和survivin在各个病理级别神经胶质瘤中的阳性表达情况,再以Spearman秩相关来分析mTOR与suivivin的相关性,探讨它们之间的生物性联系。
研究结果：
mTOR和survivin均定位于细胞核或者细胞浆,在肿瘤中呈现弥漫状分布,以在细胞内出现淡黄、棕褐色颗粒为阳性表达。mTOR在神经胶质瘤中的阳性率分别为低级别Ⅰ-Ⅱ级为37.14%(13/35),高级别Ⅲ-Ⅳ级为69.44%(25/36)；survivin的阳性表达率为低级别Ⅰ-Ⅱ级40.00%(14/35),高级别Ⅲ-Ⅳ级66.67%(24/36)；而mTOR和survivin在正常脑组织中均未见表达。根据χ2检验统计结果示,mTOR和survivin在高级别脑神经胶质瘤中的表达明显高于低级别胶质瘤,其差异具有统计学意义(P<0.01)),根据Spearman相关性检验,mTOR和survivin的表达强度均随着胶质瘤病理级别的升高而增加,其差异均具有统计学意义(rmTOR=0.470, P<0.01; rsurvivin=0.399, P<0.05); mTOR与survivin在人脑神经胶质瘤中的表达呈现相关性(rs=0.264,P=0.026<0.05)。
研究结论：
mTOR信号通路和人脑神经胶质瘤的恶性程度相关,随着神经胶质瘤病理级别的升高而表达增加；Survivin的表达在在神经胶质瘤中亦随着神经胶质瘤的病理级别的升高而表达增加,并且mTOR和survivin的表达具有一定的相关性,两者在神经胶质瘤的产生中有重要意义。因而可以推测mTOR和survivin可能在神经胶质瘤的发生发展中具有重要的作用。临床上可以考虑给予相应的单一或者联合靶向治疗,以期促进治疗方案及效果的提高。
Background
Human gliomas are one of the most common intracranial primary malignant tumors of the central nervous system.The incidence has the characteristic of "three high and one low",namely, which means the high incidence、the high mortality、the high recurrence and the low cure rate.According to the degree of malignancy,gliomas are generally divided into low grade gliomas (low-grade glioma, LGG) and high grade glioma (High-grade glioma, HGG).Grade Ⅲ、Ⅳ gliomas are regarded as malignant gliomas by the classification standard of WHO (2000).Nowadays,the treatment of operation is the main remedial method.But because of gliomas are usually invasive growth,the division with normal brain tissue is commonly not clear,It is very difficult to cut off the gliomas completely.Thus the postoperative treatment often need the combined chemotherapy or radiotherapy.Even so,the biological characteristics of gliomas often decide that it is impossible to avoid the recurrence of gliomas.Therefore,in-depth study of the pathogenesis of glioma can improve the level of diagnosis and treatment,prolong the survival time of patients.And the recurrence factors of glioma were analyzed to explore the appropriate treatment measures,which may have reduced brain gliomas recurrence rate,improve the quality of life of patients,and has certain social significance and economic value.
Objective
The etiology of human gliomas are connected with a plurality of abnormal gene expression or inhibition.The mammalian target of rapamycin (mammalian target of rapamycin,mTOR) is an atypical serine/threonine protein kinase, which is also an important signal transduction molecule. Survivin is one of the inhibitor of apoptosis protein family, which is usually only expressed in tumor or some embryonic organization. Survivin has a good specificity, and has the relationship with tumor cell proliferation and invasion metastasis. This purpose of the experiment is to determine the expression level of mTOR and survivin in glioma tissues of human brain, and to analyze the relationship of mTOR with the malignancy and prognosis of gliomas
Materials and Methods
In the study,gliomas tissues from71patients (40males and31females,average age of44.09±12.06years,rang11±68age), which were prospectively collected from the neurosurgery the of the first affiliated hospital of Zhengzhou university,According to the pathological examination,the pathological grade of glioma specimens of7cases were in grade I,14cases of grade11,22cases in grade Ⅲ,28cases of grade IV.Grade I and II of the glioma are combined to low grade group.Grade III and IV of the glioma are combined to high grade group,.Another10cases normal brain tissue of patients who were underwent the decompression as the result of the brain traumas as control group.The semi-quantitative immunohistochemistry (Envision method) were used to detect the expression intensity of mTOR and survivin.Finally,χ2test and Fisher exact were considered the appropriate methods to calculate the difference between normal brain tissue and low grade malignancy group, low grade malignancy group and high grade malignancy group.Furthermore,Spearman rank correlation analysis were used to analyze the correlation between mTOR and survivin.
Results
mTOR and Survivin were located in the nucleus or cytoplasm,which showed diffuse distribution and yellow,brown granulesin for positive expression in tumor cells.The positive rate of grade I and II of mTOR in all glioma were37.14%(13/35) and the positive rate of grade III and IV of mTOR were69.44%(25/36) of grade III and IV.The positive rate of grade I and II of survivin in all glioma were40.00%(14/35) and the positive rate of grade III and IV of survivin were66.67%(24/36) of grade III and IV.While the mTOR and Survivin in normal brain tissue had no expression.According to the statistical results of x2test and Fisher exact probability, the expression of mTOR in glioma are significantly higher than that in low grade gliomas,the difference was statistically significant (P<0.01)),the intensity of survivin expression increased with the malignant degree of glioma and the significantly. the difference was statistically significant (P<0.01).
Conclusions
The malignant degree of mTOR signal pathway have the relation with the expression of human gliomas.The expression magnitude of the mTOR in high grade gliomas than in low grade gliomas.The expression magnitude of survivin in glioma malignant also increased with the increased grade malignancy of gliomas.According to the research,mTOR and Survivin have the correlation,which also have important significance in glioma.Thus,it can be inferred that mTOR and Survivin may have the important role in the development of. gliomas. the corresponding single or combination of targeted therapy can be considered to give in clinical in order to promote and improve the effect of treatment.
引文
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[I]Yu K, Shi C, Toral-barza L, et al. Beyond rapalog therapy:preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res.2010,70 (2):621-623.
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[3]Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth [J]. Acta physiol (Oxf) 2009,196:65-80.
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[5]Ballou L M, Lin R Z. Rapamycin and mTOR kinase inhibitors [J]. Chem Biol,2008, 1 (1-4):27-36.
[6]Um S H, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K[J]. Cell Metab,2006,3 (6):393-402.
[7]Lin J N, Lin V C, Rau K M, et al. Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK actication [J]. Agric Food Chem,2010, 58 (3):1584-1592.
[8]Zhou H, Huang S. The complexes of mammalian target of rapamycin[J]. Curr Protein Pept Sci,2010,11 (6):409-424.
[9]Zhang C, Yang N, Zhang XW. Advances in kinase inhibitors targeting PI3K-Akt-mTOR signaltransduction pathway[J]. China Oncology,2006,16 (12):1064.
[10]Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth [J]. Acta physiol (Oxf) 2009,196:65-80.
[11]Sara MJ, Pat G, Isela A, et al. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling[J]. Anti-cancer Res,2009,29(8)::3185-3190.
[12]]Liu Y, Hidayat S, Su WH, et al. Expression and activity of mTOR and its substrates in different cell cycle phases and in oral squa-mous cell carcinomas of different malignant grade [J]. Cell Bio-chem Funct,2007,25(1):45-53.
[13]Zhang B, Cao H, Rao GN.15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of P13K-Akt-mTOR-S6K1 signaling [J]. Cancer Res,2005,65(16): 7283-7291.
[14]SIEGHEART W, FUEREDER T, SCHMID K, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation[J]. Transplantion,2007,83:425-432.
[15]Ning J, Li C Li H, et al. Bone marrow mesenchymal stem cells differentiate into urothelial cells and the implications for reconstructing urinary bladder mucosa[J]. Cytotechnology, 2011,63(5):531-539.
[16]Paintlia M K, Paintlia A S, Singh A K, et al. Synergistic activity of interleukin-17 and tumor necrosis factor-enhances oxidative stress-mediated oligodendrocyte apoptosis[J]. J Neurochem,2011,116(4):508-521.
[17]Clark R A, Pavlis M. Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing[J]. J Invest Dermatol,2009,129(3):529-531.
[18]Clark R A, Pavlis M. Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing[J]. J Invest Dermatol,2009,129(3):529-531.
[19]Su T R, Tsai F J, Lin J J, et al. Induction of Apoptosis by 11-Dehydrosinulariolide via Mitochondrial Dysregulation and ER Stress Pathways in Human Melanoma Cells[J]. Mar Drugs,2012,10(8):1883-1898.
[20]Huber V, De Milito A, Harguindey S, et al. Proton dynamics in cancer [J]. JTransl Med, 2010,8:57.
[21]Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer [J]. Nat Rev Cancer,2008,8(11):851-864.
[22]Martin D E, Hall M N. The expanding TOR signaling network[J]. Curr Opin Cell Biol, 2005,17(2):158-166.
[23]Chan S. Targeting the mTOR:a new approach to treating cancer. [J]. Br J Cancer,2004, 91(8):1420-1424.
[24]Hay N, Sonenberg N. Upstream and downstream of mTOR[J]. Genes Dev,2004,18(16): 1926-1945.
[25]Inoki K, Corradetti M N, Guan K L. Dysregulation of the TSC-mTOR pathway in human disease [J]. Nat Genet,2005,37(1):19-24.
[26]Yin P, Zhao C, Li Z, et al. Spl is involved in regulation of cystathionine y-lyase gene expression and biological function by PI3K/Akt pathway in human hepatocellular carcinoma cell lines [J]. Cell Signal,2012,24(6):1229-40.
[27]Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis[J]. Adv Cancer Res,2009,102:19-65.
[28]Li F. Survivin study:what is the next wave?J Cell Physiol [J].2003,197:8-29.
[29]Zhao P, Meng Q, Liu LZ, et al. Regulation of survivin by PI3K/Akt/p70S6K1 pathway[J]. Biochem Biohpys Res Commun,2010,395:219-224.
[30]S. R. Hubbard and W. T. Miller, RecePtor tyrosine kinases:meehanisms of activation and signaling[J], Curr OPin CellBiol,2007 (19):117-123.
[31]Liu DX, Hou P, Liu Z, et al. Genetic alterations in the phos-phoinosi tide 3-Kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin [J]. Cancer Res,2009,69:7311-319.
[32]Liu TJ, Dimpy K, Tiffany L, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin in-hibitor, elicits multifaceted antitumor activities in human gliomas[J]. Molecular Cancer Therapeutics,2009,8(8):2204-2210.
[33]Castellvi J, Garcia A, Rojo F, et al. Phosphorylated 4E binding pro-tein 1:Ahallmark of cell signaling that correlates with survival in ovarian cancer[J]. Cancer,2006,107(8): 1801-1811.
[34]Zhao MY, Auerbach A, D Costa AM, et al. Phospho-p70S6K/p85S6K and cdc2/cdkl are novel targets for diffuse large B-cell lymphoma combination therapy [J]. Clin Cancer Res,2009,15(15):1708-1720.
[35]Tsurutani J, West KA, Sayyah J, et al. Inhibition of the phosphatidylinositol 3-kinase /Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathwaya ttenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy [J]. Cancer Res,2005,65 (18):8423-8432.
[36]Ballas MS, Tsurutani J, Steinberg S, et al. Prognostic significance of clinical features and Akt activation in the survival of patients with bronchioloalveolar carcinoma (BAC) [J]. J Clin Oncol,2006,24 (18):7217-7219.
[37]Lin HJ, Hsieh FC, Song H, et al. Elevated phosphorylation and activation of PDK-1/ AKT pathway in human breast cancer [J]. Br J Cancer,2005,93 (12):1372-1381.
[38]Rojo F, Najera L, Lirola J, et al.4E-Binding Protein 1, A Cell Sig-naling Hallmark in Breast Cancer that Correlates with Pathologic Grade and Prognosis [J]. Clin Cancer Res, 2007,13(15):81-89.
[I]Yu K, Shi C, Toral-barza L, et al. Beyond rapalog therapy:preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res.2010,70 (2):621-623.
[2]Liu Y, Hidayat S, Su WH, et al. Expression and activity of mTOR and its substrates in different cell cycle phases and in oral squa-mous cell carcinomas of different malignant grade [J]. Cell Bio-chem Funct,2007,25(1):45-53.
[3]Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth [J]. Acta physiol (Oxf) 2009,196:65-80.
[4]Clark R A, Pavlis M. Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing[J]. J Invest Dermatol,2009,129(3):529-531.
[5]Zhang C, Yang N, Zhang XW. Advances in kinase inhibitors targeting PI3K-Akt-mTOR signaltransduction pathway[J]. China Oncology,2006,16 (12):1064.
[6]Su T R, Tsai F J, Lin J J, et al. Induction of Apoptosis by 11-Dehydrosinulariolide via Mitochondrial Dysregulation and ER Stress Pathways in Human Melanoma Cells [J]. Mar Drugs,2012,10(8):1883-1898.
[7]Li F. Survivin study:what is the next wave?J Cell Physiol [J].2003,197:8-29.
[8]Zhao P, Meng Q, Liu LZ, et al. Regulation of survivin by PI3K/Akt/p70S6K1 pathway[J]. Biochem Biohpys Res Commun,2010,395:219-224.
[9]JOHNSTON PB, ANSELL SM, COLGAN JP, et al. Phase II trial of the oral mTOR inhibitor everolimus[J]. J Clin Oncol,2007,25:8055.
[10]Ballou L M, Lin R Z. Rapamycin and mTOR kinase inhibitors [J]. Chem Biol,2008, 1 (1-4):27-36.
[11]Um S H, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K[J]. Cell Metab,2006,3 (6):393-402.
[12]Lin J N, Lin V C, Rau K M, et al. Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK actication [J]. Agric Food Chem,2010, 58 (3):1584-1592.
[13]Zhou H, Huang S. The complexes of mammalian target of rapamycin [J]. Curr Protein Pept Sci,2010,11 (6):409-424.
[14]Sara MJ, Pat G, Isela A, et al. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling [J]. Anti-cancer Res,2009,29(8):3185-3190.
[15]Zhang B, Cao H, Rao GN.15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of P13K-Akt-mTOR-S6K1 signaling [J]. Cancer Res,2005,65(16): 7283-7291.
[16]Ning J, Li C Li H, et al. Bone marrow mesenchymal stem cells differentiate into urothelial cells and the implications for reconstructing urinary bladder mucosa[J]. Cytotechnology, 2011,63(5):531-539.
[17]Inoki K, Corradetti M N, Guan K L. Dysregulation of the TSC-mTOR pathway in human disease [J]. Nat Genet,2005,37(1):19-24.
[18]Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer [J]. Nat Rev Cancer,2008,8(11):851-864.
[19]Liu DX, Hou P, Liu Z, et al. Genetic alterations in the phos-phoinositide3-Kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin [J]. Cancer Res,2009,69:7311-7319.
[20]Huber V, De Milito A, Harguindey S, et al. Proton dynamics in cancer[J]. JTransl Med, 2010,8:57.
[21]Tsurutani J, West KA, Sayyah J, et al. Inhibition of the phosphatidylinositol 3-kinase /Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathwaya ttenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy [J]. Cancer Res,2005,65 (18):8423-8432.
[22]Martin D E, Hall M N. The expanding TOR signaling network[J]. Curr Opin Cell Biol, 2005,17(2):158-166.
[23]Chan S. Targeting the mTOR:a new approach to treating cancer. [J]. Br J Cancer,2004, 91(8):1420-1424.
[24]Clark R A, Pavlis M. Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing[J]. J Invest Dermatol,2009,129(3):529-531.
[25]Petricoin EF 3rd, Espina V, Araujo RP, et al. Phosphoprotein Pathway Mapping: Akt/Mammalian Target of Rapamycin Activation Is Negatively Associated with Childhood Rhabdomyosarcoma Sur-vival [J]. Cancer Res,2007,67(7):3431-3440.
[26]Liang XJ, Aszalos A. Multidrug transporters as drug targets[J]. Curr Drug Targets,2006, 7(8):911-921.
[27]S. R. Hubbard and W. T. Miller, RecePtor tyrosine kinases:meehanisms of activation and signaling[J], Curr OPin CellBiol,2007 (19):117-123.
[28]SIEGHEART W, FUEREDER T, SCHMC D K, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation[J]. Transplantion,2007,83:425-432.
[29]Paintlia M K, Paintlia A S, Singh A K, et al. Synergistic activity of interleukin-17 and tumor necrosis factor-a enhances oxidative stress-mediated oligodendrocyte apoptosis[J]. J Neurochem,2011,116(4):508-521.
[30]Clark R A, Pavlis M. Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing[J]. J Invest Dermatol,2009,129(3):529-531.
[31]Hay N, Sonenberg N. Upstream and downstream of mTOR[J]. Genes Dev,2004,18(16): 1926-1945.
[32]Yin P, Zhao C, Li Z, et al. Spl is involved in regulation of cystathionine γ-lyase gene expression and biological function by PI3K/Akt pathway in human hepatocellular carcinoma cell lines [J]. Cell Signal,2012,24(6):1229-40.
[33]Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis[J]. Adv Cancer Res,2009,102:19-65.
[34]Liu TJ, Dimpy K, Tiffany L, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin in-hibitor, elicits multifaceted antitumor activities in human gliomas[J]. Molecular Cancer Therapeutics,2009,8(8):2204-2210.
[35]Castellvi J, Garcia A, Rojo F, et al. Phosphorylated 4E binding pro-tein 1:A hallmark of cell signaling that correlates with survival in ovarian cancer [J]. Cancer,2006,107(8): 1801-1811.
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