Six4蛋白在结肠癌中的表达及临床意义
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摘要
目的:探索Six4蛋白在结肠癌中的表达及其与临床特征的关联性.方法:通过医学癌症数据库分析Six4表达与结肠癌患者生存时间的相关性;利用组织芯片,通过免疫组化检测结肠癌组织及癌旁组织中Six4蛋白的表达情况,统计分析其表达差异,分析Six4蛋白表达与结肠癌患者的临床特征及预后的关系.结果:Six4高表达结肠癌患者生存期较低表达患者明显缩短(P=0.002).在结肠癌组织中Six4蛋白表达显著高于癌旁组织(P<0.001).Six4表达水平与结肠癌患者病理分期(P=0.020)、肿瘤大小(P=0.034)、MSH6表达水平(P=0.035)有相关性,而与性别、年龄、淋巴结转移、是否远处转移、TNM分期、Ki67、P53、MSH2蛋白表达水平无明显相关性.Six4蛋白的表达水平(P=0.029)可以作为结肠癌患者的独立预后因素.结论:Six4蛋白高表达与不良预后相关;Six4蛋白在结肠癌组织较癌旁组织高表达;Six4蛋白与病理分期、肿瘤大小、MSH6表达水平相关.
Objective:To explore the expression and significance of Six4 in colorectal carcinoma tissues. Methods: Analyze the relationship between Six4 expression and survival time of CRC patients. The immunohistochemical SP was used to detect the expression of Six4 protein in CRC tissues and adjacent tissues, statistically analyzed the different expression and the relationship between Six4 protein expression and clinical factors and prognosis of CRC. Results: The survival time of CRC patients with high Six4 expression was significantly shorter than that of patients with low Six4 expression(P=0.002). The expression of Six4 protein was significantly higher in CRC than in adjacent normal tissues.Six4 expression was significantly correlated with pathological stage(P=0.020), tumor size(P=0.034), the expression level of MSH6(P=0.035),but not with gender, age, lymph node metastasis, distant metastasis, TNM stage, expression levels of Ki67, P53 and MSH2.The expression level of Six4(P=0.029) was independent prognostic factors for CRC patients. Conclusion:High expression of Six4 protein was associated with poor prognosis. Six4 was highly expressed in CRC tissues compared to adjacent normal tissues; With Pathological stage, tumor size, MSH6 expression level related, the expression level of Six4 served as an independent prognostic factor for patients with CRC. Six4 protein plays an important role in the development of CRC.
Objective:To explore the expression and significance of Six4 in colorectal carcinoma tissues. Methods: Analyze the relationship between Six4 expression and survival time of CRC patients. The immunohistochemical SP was used to detect the expression of Six4 protein in CRC tissues and adjacent tissues, statistically analyzed the different expression and the relationship between Six4 protein expression and clinical factors and prognosis of CRC. Results: The survival time of CRC patients with high Six4 expression was significantly shorter than that of patients with low Six4 expression(P=0.002). The expression of Six4 protein was significantly higher in CRC than in adjacent normal tissues.Six4 expression was significantly correlated with pathological stage(P=0.020), tumor size(P=0.034), the expression level of MSH6(P=0.035),but not with gender, age, lymph node metastasis, distant metastasis, TNM stage, expression levels of Ki67, P53 and MSH2.The expression level of Six4(P=0.029) was independent prognostic factors for CRC patients. Conclusion:High expression of Six4 protein was associated with poor prognosis. Six4 was highly expressed in CRC tissues compared to adjacent normal tissues; With Pathological stage, tumor size, MSH6 expression level related, the expression level of Six4 served as an independent prognostic factor for patients with CRC. Six4 protein plays an important role in the development of CRC.
引文
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[17] KONISHI Y,IKEDA K,IWAKURA Y,et al.Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis[J].Brain Research,2006,1116(1):93-102.
[18] SUZUKI Y,IKEDA K,KAWAKAMI K.Expression of Six1 and Six4 in mouse taste buds[J].Journal of Molecular Histology,2010,41(4/5):205-214.
[19] CHEN B,KIM E H,XU P X,et al.Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4[J].Developmental Biology,2009,326(1):75-85.
[20] GARCEZ R C,LE DOUARIN N M,CREUZET S E.Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development[J].Cellular & Molecular Life Sciences Cmls,2014,71(11):2149-2164.
[21] MAIRE P.New insights into adult muscle fiber-type diversity:involvement of Six homeoproteins[J].Bulletin de l'Academie Nationale De Medecine,2015,199(1):21-31.
[22] LI G,HU F,LUO X,et al.SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer[J].Peer J,2017,5:e3394.doi:10.7717/peerj.3394.
[23] MISONO S,SEKI N,MIZUNO K,et al.Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis[J].Journal of Human Genetics,2018,63(10):1015-1028.
[2] 宋文,彭曼,段世玉,等.MIER3在结直肠癌中的表达及其相关蛋白的生物信息学分析[J].南方医科大学学报,2017,37(8):1040-1046.SONG W,PENG M,DUAN S Y,et al.Expression of MIER3 in colorectal cancer and bioinformatic analysis of MIER3 interacting proteins.[J].Journal of Southern Medical University,2017,37(8):1040-1046.
[3] 郑荣寿,孙可欣,张思维,等.2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志,2019,41(1):19-28.doi:10.3760/cma.j.issn.0253-3766.2019.01.005.ZHENG R S,SUN K X,ZHANG S W,et al.Report of cancer epidemiology in China,2015[J].Chinese Journal of Oncology,2019,41(1):19-28.doi:10.3760/cma.j.issn.0253-3766.2019.01.005.
[4] COOPER J B,RONECKER J S,TOBIAS M E,et al.Molecular sequence of events and signaling pathways in cerebral metastases[J].Anticancer Research,2018,38(4):1859-1877.
[5] 魏巧,郁玮玮,赵快乐,等.Six1和Six4在食管鳞状细胞癌组织中的表达及其与预后的关系[J].中华病理学杂志,2013,42(7):446-450.WEI Q,YU W W,ZHAO K L,et al.Expression of Six1 and Six4 in esophageal squamous cell carcinoma and their correlation with clinical prognosis[J].Chinese Journal of Pathology,2013,42(7):446-450.
[6] XU H X,WU K J,TIAN Y J,et al.Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer:A systematic review and meta-analysis[J].Medicine,2016,95(27):e4085.
[7] NA X Y,SHANG X S,ZHAO Y,et al.MiR-203a functions as a tumor suppressor in bladder cancer by targeting SIX4[J].Neoplasma,2019,66(2):211-221.
[8] LIU Q,LI A P,TIAN Y J,et al.The expression profile and clinic significance of the SIX family in non-small cell lung cancer[J].Journal of Hematology & Oncology,2016,9(1):119.
[9] HUYGHE J R,BIEN S A,HARRISON T A,et al.Discovery of common and rare genetic risk variants for colorectal cancer[J].Nature Genetics,2019,51(1):76-87.
[10] 向梦,张婷,张宗泽.结肠癌相关生物标记物和信号通路的生物信息学筛选[J].胃肠病学,2018,23(8):466-471.XIANG M,ZHANG T,ZHANG Z Z,et al.Identification of candidate biomarkers and pathways in colon cancer by bioinformatics analysis[J].Chinese Journal of Gastroenterology,2018,23(8):466-471.
[11] ARMAT M,RAMEZANI F,MOLAVI O,et al.Six family of homeobox genes and related mechanisms in tumorigenesis protocols[J].Tumori,2016,2016(3):236-243.
[12] SHU S,MAMEDOVA A,HEGDE R S.DNA-binding and regulation mechanisms of the SIX family of retinal determination proteins[J].Biochemistry,2008,47(11):3586-3594.
[13] ZHANG J,JIANG T Y,JIANG B G,et al.RMP predicts survival and adjuvant TACE response in hepatocellular carcinoma[J].Oncotarget,2015,6(5):3432-3442.
[14] TAKAHASHI M,TAMURA M,SATO S,et al.Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele[J].Disease Models & Mechanisms,2018,11(10):pii:dmm034611.doi:10.1242/dmm.034611.
[15] WANG J,LIU M,ZHAO L,et al.Disabling of nephrogenesis in porcine embryos via CRISPR/Cas9-mediated SIX1 and SIX4 gene targeting[J].Xenotransplantation,2019,9:e12484.doi:10.1111/xen.12484.
[16] ZHANG Y,ZHAO B,ROY S,et al.MicroRNA-309 targets the Homeobox gene SIX4 and controls ovarian development in the mosquito Aedes aegypti[J].Proceedings of the National Academy of Sciences of the United States of America,2016,113(33):E4828-E4836.
[17] KONISHI Y,IKEDA K,IWAKURA Y,et al.Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis[J].Brain Research,2006,1116(1):93-102.
[18] SUZUKI Y,IKEDA K,KAWAKAMI K.Expression of Six1 and Six4 in mouse taste buds[J].Journal of Molecular Histology,2010,41(4/5):205-214.
[19] CHEN B,KIM E H,XU P X,et al.Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4[J].Developmental Biology,2009,326(1):75-85.
[20] GARCEZ R C,LE DOUARIN N M,CREUZET S E.Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development[J].Cellular & Molecular Life Sciences Cmls,2014,71(11):2149-2164.
[21] MAIRE P.New insights into adult muscle fiber-type diversity:involvement of Six homeoproteins[J].Bulletin de l'Academie Nationale De Medecine,2015,199(1):21-31.
[22] LI G,HU F,LUO X,et al.SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer[J].Peer J,2017,5:e3394.doi:10.7717/peerj.3394.
[23] MISONO S,SEKI N,MIZUNO K,et al.Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis[J].Journal of Human Genetics,2018,63(10):1015-1028.