Claudin-3在结直肠癌中的表达及意义
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摘要
目的观察在结直肠癌组织中紧密连接蛋白claudin-3的表达,探讨claudin-3与结直肠癌发生、发展、转移及预后的关系。方法收集南方医院2010年10月~2013年1月间手术切除结直肠癌组织40例(癌组)及癌旁正常结直肠粘膜组织22例(癌旁正常组)。应用免疫组化法检测组织中claudin-3的表达水平。分析和比较癌组不同病理参数和不同存活情况病例间的claudin-3蛋白表达情况。结果 claudin-3蛋白的表达主要分布在细胞膜上。癌组阳性表达率为92.50%,显著高于癌旁正常组的59.09%(P<0.05)。13例来自同一患者的癌组织和癌旁正常组织的claudin-3表达平均评分(染色强度评分+阳性细胞所占比例评分)分别为4.538和3.269(P=0.019)。在40例癌组患者中,高分化组、中分化组、低分化组claudin-3的强阳性表达率分别为21.43%、36.84%和85.71%,其中高分化组与低分化组间及低分化组与中分化组间的差异均有统计学意义(P<0.05);淋巴结转移组claudin-3强阳性率为61.11%,显著高于无淋巴结转移组的22.72%(P<0.05);在不同年龄、性别、肿瘤部位、肿瘤最长径的分组间,claudin-3强阳性表达率差异均无统计学意义(P>0.05)。随访癌组的40例患者,失访7例,术后生存期≤3年14例(死亡组),生存期>3年19例(存活组),两组claudin-3表达平均评分分别为4.50和3.526(P<0.05)。结论结直肠癌组织中claudin-3的表达显著升高,claudin-3的高强度表达可能促进了结直肠癌的发生及发展过程,并可能成为结直肠癌早期诊断及判断预后的分子生物学指标。
Objective To investigate the expression of claudin-3 in colorectal carcinoma and its association with the occurrence,progression and prognosis of colorectal cancer. Methods Forty surgical specimens of colorectal carcinoma and 22 adjacent normal tissues resected between October, 2010 and January, 2013 at Nanfang Hospital were examined for claudin-3 expression using immunohistochemistry, which was analyzed in association with the clinicopathological parameters and the survival of the patients. Results Claudin-3 was expressed mainly on the cell membrane, and its positivity rate was significantly higher in cancer tissues than in normal tissues(92.50% vs 59.09%, P<0.05). In 13 cases claudin- 3 expression was detected in both the cancer tissues and adjacent normal tissues with average expression scores of 4.538 and 3.269, respectively(P<0.05). In the cancer tissues, the strongly positive expression rate was significantly higher in poorly differentiated tissues(85.71%) than in well(21.43%) and moderately(36.48%) differentiated tissues(P<0.05), and was higher in cases with lymph node metastasis than in those without(61.11% vs 22.72%, P<0.05). The strongly positive expression rate of claudin-3 was not correlated with the patients' age, gender, tumor location or tumor size(P>0.05). Of the 33 cancer patients followed up, 14 had a postoperative survival time no longer than 3 years and 19 had longer survival time, and their average expression scores differed significantly(4.50 vs 3.526, P<0.05). Conclusion Claudin- 3 is over- expressed in colorectal cancer tissues, and its high expression may promote the occurrence and progression of colorectal cancer. Claudin- 3 may serve as a molecular biomarker for early diagnosis and prognostic evaluation.
Objective To investigate the expression of claudin-3 in colorectal carcinoma and its association with the occurrence,progression and prognosis of colorectal cancer. Methods Forty surgical specimens of colorectal carcinoma and 22 adjacent normal tissues resected between October, 2010 and January, 2013 at Nanfang Hospital were examined for claudin-3 expression using immunohistochemistry, which was analyzed in association with the clinicopathological parameters and the survival of the patients. Results Claudin-3 was expressed mainly on the cell membrane, and its positivity rate was significantly higher in cancer tissues than in normal tissues(92.50% vs 59.09%, P<0.05). In 13 cases claudin- 3 expression was detected in both the cancer tissues and adjacent normal tissues with average expression scores of 4.538 and 3.269, respectively(P<0.05). In the cancer tissues, the strongly positive expression rate was significantly higher in poorly differentiated tissues(85.71%) than in well(21.43%) and moderately(36.48%) differentiated tissues(P<0.05), and was higher in cases with lymph node metastasis than in those without(61.11% vs 22.72%, P<0.05). The strongly positive expression rate of claudin-3 was not correlated with the patients' age, gender, tumor location or tumor size(P>0.05). Of the 33 cancer patients followed up, 14 had a postoperative survival time no longer than 3 years and 19 had longer survival time, and their average expression scores differed significantly(4.50 vs 3.526, P<0.05). Conclusion Claudin- 3 is over- expressed in colorectal cancer tissues, and its high expression may promote the occurrence and progression of colorectal cancer. Claudin- 3 may serve as a molecular biomarker for early diagnosis and prognostic evaluation.
引文
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[18]Nübel T,Preobraschenski J,Tuncay H,et al.Claudin-7 regulates Ep CAM-mediated functions in tumor progression[J].Mol Cancer Res,2009,7(3):285-99.
[19]Takehara M,Nishimura T,Mima S,et al.Effect of claudin expression on paracellular permeability,migration and invasion of colonic cancer cells[J].Biol Pharm Bull,2009,32(5):825-31.
[20]de Souza WF,Fortunato-Miranda N,Robbs BK,et al.Claudin-3overexpression increases the malignant potential of colorectal cancer cells:roles of ERK1/2 and PI3K-Akt as modulators of EGFR signaling[J].PLo S One,2013,8(9):e74994.
[21]Takala H,Saarnio J,Wiik H,et al.Claudins 1,3,4,5 and 7 in esophageal cancer:loss of claudin 3 and 4 expression is associated with metastatic behavior[J].APMIS,2007,115(7):838-47.
[22]姚永强,韩雪,曹铭谦,等.紧密连接蛋白Claudin-3在人乳腺癌组织的表达与临床意义[J].现代中西医结合杂志,2014(30):3329-31.
[23]Long H,Crean CD,Lee WH,et al.Expression of clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium[J].Cancer Res,2001,61(21):7878-81.
[24]English DP,Santin AD.Claudins overexpression in ovarian cancer:potential targets for Clostridium Perfringens Enterotoxin(CPE)based diagnosis and therapy[J].Int J Mol Sci,2013,14(5):10412-37.
[25]Che J,Yang Y,Xiao J,et al.Decreased expression of claudin-3 is associated with a poor prognosis and EMT in completely resected squamous cell lung carcinoma[J].Tumour Biol,2015,36(8):6559-68.
[26]Jiang L,Yang D,Fu L,et al.CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma[J].Oncotarget,2014,5(17):7663-76.
[2]Sánchez-TillóE,de Barrios O,Siles L,et al.β-catenin/TCF4complex induces the epithelial-to-mesenchymal transition(EMT)-activator ZEB1 to regulate tumor invasiveness[J].Proc Natl Acad Sci USA,2011,108(48):19204-9.
[3]Wang H,Yang X.The expression patterns of tight junction protein claudin-1,-3,and-4 in human gastric neoplasms and adjacent nonneoplastic tissues[J].Int J Clin Exp Pathol,2015,8(1):881-7.
[4]Karabulut M,Alis H,Bas K,et al.Clinical significance of serum claudin-1 and claudin-7 levels in patients with colorectal cancer[J].Mol Clin Oncol,2015,3(6):1255-67.
[5]de Oliveira S,de Oliveira M,De Souza W,et al.Claudins upregulation in human colorectal cancer[J].FEBS Lett,2005,579(27):6179-85.
[6]马兰芳.claudi N-3.claudin-4在结直肠腺瘤和结直肠癌中的表达[D].石家庄:河北医科大学,2015.
[7]Oliveira SS,Morgado-Díaz JA.Claudins:multifunctional players in epithelial tight junctions and their role in cancer[J].Cell Mol Life Sci,2007,64(1):17-28.
[8]Soini Y.Expression of claudins 1,2,3,4,5 and 7 in various types of tumours[J].Histopathology,2005,46(5):551-60.
[9]Hossain Z,Hirata T.Molecular mechanism of intestinal permeability:interaction at tight junctions[J].Mol Biosyst,2008,4(12):1181-5.
[10]Lee B,Huang E,Ward J.Tight junction biology and kidney dysfunction[J].Am J Physiol Renal Physiol,2006,290(1):F20-34.
[11]Khan N,Asif R.Transcriptional regulators of claudins in epithelial tight junctions[J].Mediators Inflamm,2015:219843.
[12]王琳,李世拥.CLDN在结直肠癌组织中的表达及研究进展[J].肿瘤学杂志,2012,18(6):470-4.
[13]Morin PJ.Claudin proteins in human cancer:promising new targets for diagnosis and therapy[J].Cancer Res,2005,65(21):9603-6.
[14]Webb PG,Spillman MA,Baumgartner HK.Claudins play a role in normal and tumor cell motility[J].BMC Cell Biol,2013,14:19.
[15]邵瑞颖,石莎,李森林.紧密连接蛋白Claudins与胃癌关系的研究进展[J].胃肠病学和肝病学杂志,2015,24(10):1171-4.
[16]Soler AP,Miller RD,Laughlin KV,et al.Increased tight junctional permeability is associated with the development of colon cancer[J].Carcinogenesis,1999,20(8):1425-31.
[17]Mees ST,Mennigen R,Spieker T,et al.Expression of tight and adherens junction proteins in ulcerative colitis associated colorectal carcinoma:upregulation of claudin-1,claudin-3,claudin-4,and beta-catenin[J].Int J Colorectal Dis,2009,24(4):361-8.
[18]Nübel T,Preobraschenski J,Tuncay H,et al.Claudin-7 regulates Ep CAM-mediated functions in tumor progression[J].Mol Cancer Res,2009,7(3):285-99.
[19]Takehara M,Nishimura T,Mima S,et al.Effect of claudin expression on paracellular permeability,migration and invasion of colonic cancer cells[J].Biol Pharm Bull,2009,32(5):825-31.
[20]de Souza WF,Fortunato-Miranda N,Robbs BK,et al.Claudin-3overexpression increases the malignant potential of colorectal cancer cells:roles of ERK1/2 and PI3K-Akt as modulators of EGFR signaling[J].PLo S One,2013,8(9):e74994.
[21]Takala H,Saarnio J,Wiik H,et al.Claudins 1,3,4,5 and 7 in esophageal cancer:loss of claudin 3 and 4 expression is associated with metastatic behavior[J].APMIS,2007,115(7):838-47.
[22]姚永强,韩雪,曹铭谦,等.紧密连接蛋白Claudin-3在人乳腺癌组织的表达与临床意义[J].现代中西医结合杂志,2014(30):3329-31.
[23]Long H,Crean CD,Lee WH,et al.Expression of clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium[J].Cancer Res,2001,61(21):7878-81.
[24]English DP,Santin AD.Claudins overexpression in ovarian cancer:potential targets for Clostridium Perfringens Enterotoxin(CPE)based diagnosis and therapy[J].Int J Mol Sci,2013,14(5):10412-37.
[25]Che J,Yang Y,Xiao J,et al.Decreased expression of claudin-3 is associated with a poor prognosis and EMT in completely resected squamous cell lung carcinoma[J].Tumour Biol,2015,36(8):6559-68.
[26]Jiang L,Yang D,Fu L,et al.CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma[J].Oncotarget,2014,5(17):7663-76.