PKG、PKA及VASP在人结直肠癌组织中的表达及临床意义
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摘要
目的探讨cGMP依赖性蛋白激酶(PKG)两种亚型PKG-Ⅰ和PKG-Ⅱ、cAMP依赖性蛋白激酶A(PKA)、血管扩张刺激磷蛋白(VASP)及其两种磷酸化蛋白p-VASP Ser157和p-VASP Ser239在结直肠癌(CRC)组织中的表达水平及临床意义。方法收集云南省肿瘤医院结直肠外科2015年3-9月收治的20例有完整病理资料的CRC患者通过手术切除获得的癌组织及其同源的正常癌旁组织,用Western blot检测上述组织中的PKG-Ⅰ、PKG-Ⅱ、PKA、VASP、p-VASP Ser157和p-VASP Ser239的蛋白表达水平,进行统计分析。同时,分析这些蛋白表达与年龄、性别等病理数据的相关性。结果 CRC组织中的PKG-Ⅰ、PKG-Ⅱ、VASP、p-VASP Ser157和p-VASP Ser239的蛋白表达均显著低于正常的癌旁组织(P<0.05),而PKA差异无统计学意义(P>0.05);并且所有蛋白因子和性别、年龄、肿瘤分化程度及TNM分期等一般病理数据无显著性相关。结论 PKG两种亚型与VASP及其两种磷酸化蛋白在CRC组织显著降低,可能会成为临床诊断治疗CRC的新靶点。
Objective To investigate the expressions and clinical significances of cGMP-dependent protein kinase(PKG)type I(PKG-Ⅰ)and type II(PKG-Ⅱ),cAMP-dependent protein kinase(PKA),vasodilator-stimulated phosphoprotein(VASP)and phosphorylation of VASP including p-VASP Ser157 and p-VASP Ser239 in colorectal cancer(CRC).Methods CRC tissues and their homologous normal paracancerous tissues surgically of 20 patients with complete pathological data from March 2015 to September 2015 admitted to the colorectal surgery department of Yunnan Cancer Hospital were collected.The protein expressions of PKG-Ⅰ,PKG-Ⅱ,VASP,p-VASP Ser157,and p-VASP Ser239 in the above tissues were performed by Western blot.The correlation between these protein expression and general pathology data were analyzed.Results In CRC tissues,protein expressions of PKG-Ⅰ,PKG-Ⅱ,VASP,p-VASP Ser157 and p-VASP Ser239 were significantly lower than those in the normal tissues(P<0.05)while PKA difference was not statistically significant(P>0.05).In addition,there was no significant correlation between all protein factors and general pathological data such as gender,age,tumor differentiation degree and TNM stage.Conclusion Two subtypes of PKG,VASP and its two phosphorylated proteins significantly reduced in CRC tissues,which may be potential targets for CRC therapy.
Objective To investigate the expressions and clinical significances of cGMP-dependent protein kinase(PKG)type I(PKG-Ⅰ)and type II(PKG-Ⅱ),cAMP-dependent protein kinase(PKA),vasodilator-stimulated phosphoprotein(VASP)and phosphorylation of VASP including p-VASP Ser157 and p-VASP Ser239 in colorectal cancer(CRC).Methods CRC tissues and their homologous normal paracancerous tissues surgically of 20 patients with complete pathological data from March 2015 to September 2015 admitted to the colorectal surgery department of Yunnan Cancer Hospital were collected.The protein expressions of PKG-Ⅰ,PKG-Ⅱ,VASP,p-VASP Ser157,and p-VASP Ser239 in the above tissues were performed by Western blot.The correlation between these protein expression and general pathology data were analyzed.Results In CRC tissues,protein expressions of PKG-Ⅰ,PKG-Ⅱ,VASP,p-VASP Ser157 and p-VASP Ser239 were significantly lower than those in the normal tissues(P<0.05)while PKA difference was not statistically significant(P>0.05).In addition,there was no significant correlation between all protein factors and general pathological data such as gender,age,tumor differentiation degree and TNM stage.Conclusion Two subtypes of PKG,VASP and its two phosphorylated proteins significantly reduced in CRC tissues,which may be potential targets for CRC therapy.
引文
[1]MORADI MARJANEH R,HASSANIAN S M,GHOBA-DI N,et al.Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer[J].J Cell Physiol,2018,233(10):6538-6549.
[2]ARNOLD M,SIERRA M S,LAVERSANNE M A,et al.Global patterns and trends in colorectal cancer incidence and mortality[J].Gut,2017,66(4):683-691.
[3]MORADI-MARJANEH R,HASSANIAN S M,FIUJI H,et al.Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer[J].J Cell Physiol,2018,233(8):5613-5622.
[4]CHEN W Q ZHENG R S,BAADE P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[5]陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤,2018,27(1):1-14.
[6]DU X H,CHEN C,ZHANG M,et al.Scutellarin reduces endothelium dysfunction through the PKG-I pathway[J].Evid Based Complement Alternat Med,2015(1):430271.
[7]LI L,LI L,CHEN C,et al.Scutellarin′s cardiovascular endothelium protective mechanism:important role of PKG-Iα[J].PLoS One,2015,10(10):e0139570.
[8]TABRIZIAN K,HASHEMZAEI M,NASIRI A A,et al.Interactive involvement of hippocampal cAMP/PKA and cyclooxygenase-2signaling pathways in spatial learning in the Morris water maze[J].Folia Neuropathologica,2018,56(1):58-66.
[9]HU Y F,PAN S Y,ZHANG H T.Interaction of Cdk5and cAMP/PKA signaling in the mediation of neuropsychiatric and neurodegenerative diseases[J].Advances in neurobiology,2017,17(1):45-61.
[10]HU L D,ZOU H F,ZHAN S X,et al.EVL(Ena/VASP-like)expression is up-regulated in human breast cancer and its relative expression level is correlated with clinical stages[J].Oncol Rep,2008,19(4):1015-1020.
[11]BENSON A B,VENOOK A P,CEDERQUIST L,et al.Colon cancer,version 1.2017,NCCN clinical practice guidelines in oncology[J].J Natl Compr Canc Netw,2017,15(3):370-398.
[12]JOHNSTON S,WILSON K,VARKER H A,et al.Realworld direct health care costs for metastatic colorectal cancer patients treated with cetuximab or bevacizumabcontaining regimens in first-line or first-line through second-line therapy[J].Clin Colorectal Cancer,2017,16(4):386.
[13]MATIC I Z,KOLUNDZIJA B,DAMJANOVIC A,et al.Peripheral white blood cell subsets in metastatic colorectal cancer patients treated with cetuximab:the potential clinical relevance[J].Front Immunol,2017,8(1):1886.
[14]DESANTIS C E,LIN C C,MARIOTTO A B,et al.Cancer treatment and survivorship statistics,2014[J].CACancer J Clin,2014,64(4):252-271.
[15]RAHBI H,NARAYAN H,JONES D J,et al.The uroguanylin system and human disease[J].Clin Sci(Lond),2012,123(12):659-668.
[16]MACHESKY L.Putting on the brakes:a negative regulatory function for ENA/VASP proteins in cell migration[J].Cell,2000,101(7):685-688.
[17]WALDKIRCH E,UCKERT S,LANGNASE K,et al.Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1in human prostate tissue[J].Eur Urol,2007,52(2):495-501.
[18]KWON I K,SCHOENLEIN P V,DELK J,et al.Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis[J].Cancer,2008,112(7):1462-1470.
[19]FALLAHIAN F,KARAMI-TEHRANI F,SALAMI S,et al.Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and-negative breast cancer cell lines[J].FEBS J,2011,278(18):3360-3369.
[20]钱晶,蒋学通,徐传奇,等.cGMP/PKA通路在结直肠癌肝转移中的作用及机制研究[J].中华结直肠疾病电子杂志,2016,5(3):244-248.
[21]TINSLEY H N,GARY B D,THAIPARAMBIL J,et al.Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5inhibition[J].Cancer Prev Res(Phila),2010,3(10):1303-1313.
[22]LEIPHRAKPAM P D,BRATTAIN M G,BLACK J D,et al.TGFβand IGF1Rsignaling activates protein kinase Athrough differential regulation of ezrin phosphorylation in colon cancer cells[J].J Biol Chem,2018,293(21):8242-8254.
[23]BABYKUTTY S,SUBOJ P,SRINIVAS P,et al.Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9via activation of cGMP-PKG-ERK signaling pathways[J].Clin Exp Metastasis,2012,29(5):471-492.
[24]FRANCIS S H,BLOUNT M A,CORBIN J D.Mammalian cyclic nucleotide phosphodiesterases:molecular mechanisms and physiological functions[J].Physiol Rev,2011,91(2):651-690.
[25]LEE K,APIAZZA G.The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer[J].J Biomed Res,2017,31(3):189-196.
[26]ZUZGA D S,PELTA-HELLER J,LI P,et al.Phosphorylation of vasodilator-stimulated phosphoprotein Ser239suppresses filopodia and invadopodia in colon cancer[J].Internat J Cancer,2012,130(11):2539-2548.
[27]宋胜江,孙利敏,徐定银,等.VASP在结肠癌组织中的表达及其对预后的影响[J].实用肿瘤杂志,2016,31(01):48-52.
[28]ALI M,ROGERS L K,PITARI G M.Serine phosphorylation of vasodilator-stimulated phosphoprotein(VASP)regulates colon cancer cell survival and apoptosis[J].Life Sci,2015,123(1):1-8.
[2]ARNOLD M,SIERRA M S,LAVERSANNE M A,et al.Global patterns and trends in colorectal cancer incidence and mortality[J].Gut,2017,66(4):683-691.
[3]MORADI-MARJANEH R,HASSANIAN S M,FIUJI H,et al.Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer[J].J Cell Physiol,2018,233(8):5613-5622.
[4]CHEN W Q ZHENG R S,BAADE P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[5]陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤,2018,27(1):1-14.
[6]DU X H,CHEN C,ZHANG M,et al.Scutellarin reduces endothelium dysfunction through the PKG-I pathway[J].Evid Based Complement Alternat Med,2015(1):430271.
[7]LI L,LI L,CHEN C,et al.Scutellarin′s cardiovascular endothelium protective mechanism:important role of PKG-Iα[J].PLoS One,2015,10(10):e0139570.
[8]TABRIZIAN K,HASHEMZAEI M,NASIRI A A,et al.Interactive involvement of hippocampal cAMP/PKA and cyclooxygenase-2signaling pathways in spatial learning in the Morris water maze[J].Folia Neuropathologica,2018,56(1):58-66.
[9]HU Y F,PAN S Y,ZHANG H T.Interaction of Cdk5and cAMP/PKA signaling in the mediation of neuropsychiatric and neurodegenerative diseases[J].Advances in neurobiology,2017,17(1):45-61.
[10]HU L D,ZOU H F,ZHAN S X,et al.EVL(Ena/VASP-like)expression is up-regulated in human breast cancer and its relative expression level is correlated with clinical stages[J].Oncol Rep,2008,19(4):1015-1020.
[11]BENSON A B,VENOOK A P,CEDERQUIST L,et al.Colon cancer,version 1.2017,NCCN clinical practice guidelines in oncology[J].J Natl Compr Canc Netw,2017,15(3):370-398.
[12]JOHNSTON S,WILSON K,VARKER H A,et al.Realworld direct health care costs for metastatic colorectal cancer patients treated with cetuximab or bevacizumabcontaining regimens in first-line or first-line through second-line therapy[J].Clin Colorectal Cancer,2017,16(4):386.
[13]MATIC I Z,KOLUNDZIJA B,DAMJANOVIC A,et al.Peripheral white blood cell subsets in metastatic colorectal cancer patients treated with cetuximab:the potential clinical relevance[J].Front Immunol,2017,8(1):1886.
[14]DESANTIS C E,LIN C C,MARIOTTO A B,et al.Cancer treatment and survivorship statistics,2014[J].CACancer J Clin,2014,64(4):252-271.
[15]RAHBI H,NARAYAN H,JONES D J,et al.The uroguanylin system and human disease[J].Clin Sci(Lond),2012,123(12):659-668.
[16]MACHESKY L.Putting on the brakes:a negative regulatory function for ENA/VASP proteins in cell migration[J].Cell,2000,101(7):685-688.
[17]WALDKIRCH E,UCKERT S,LANGNASE K,et al.Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1in human prostate tissue[J].Eur Urol,2007,52(2):495-501.
[18]KWON I K,SCHOENLEIN P V,DELK J,et al.Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis[J].Cancer,2008,112(7):1462-1470.
[19]FALLAHIAN F,KARAMI-TEHRANI F,SALAMI S,et al.Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and-negative breast cancer cell lines[J].FEBS J,2011,278(18):3360-3369.
[20]钱晶,蒋学通,徐传奇,等.cGMP/PKA通路在结直肠癌肝转移中的作用及机制研究[J].中华结直肠疾病电子杂志,2016,5(3):244-248.
[21]TINSLEY H N,GARY B D,THAIPARAMBIL J,et al.Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5inhibition[J].Cancer Prev Res(Phila),2010,3(10):1303-1313.
[22]LEIPHRAKPAM P D,BRATTAIN M G,BLACK J D,et al.TGFβand IGF1Rsignaling activates protein kinase Athrough differential regulation of ezrin phosphorylation in colon cancer cells[J].J Biol Chem,2018,293(21):8242-8254.
[23]BABYKUTTY S,SUBOJ P,SRINIVAS P,et al.Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9via activation of cGMP-PKG-ERK signaling pathways[J].Clin Exp Metastasis,2012,29(5):471-492.
[24]FRANCIS S H,BLOUNT M A,CORBIN J D.Mammalian cyclic nucleotide phosphodiesterases:molecular mechanisms and physiological functions[J].Physiol Rev,2011,91(2):651-690.
[25]LEE K,APIAZZA G.The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer[J].J Biomed Res,2017,31(3):189-196.
[26]ZUZGA D S,PELTA-HELLER J,LI P,et al.Phosphorylation of vasodilator-stimulated phosphoprotein Ser239suppresses filopodia and invadopodia in colon cancer[J].Internat J Cancer,2012,130(11):2539-2548.
[27]宋胜江,孙利敏,徐定银,等.VASP在结肠癌组织中的表达及其对预后的影响[J].实用肿瘤杂志,2016,31(01):48-52.
[28]ALI M,ROGERS L K,PITARI G M.Serine phosphorylation of vasodilator-stimulated phosphoprotein(VASP)regulates colon cancer cell survival and apoptosis[J].Life Sci,2015,123(1):1-8.