Claudin-1和Claudin-10在肝细胞癌中的表达及意义
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摘要
目的:研究紧密连接蛋白Claudin-1和Claudin-10在肝细胞癌(hepatocellar carcinoma、HCC)组织、癌旁组织和正常肝组织中的表达情况,探讨Claudin-1和Claudin-10表达与HCC发生及其预后的关系。
方法:采用实时荧光定量PCR(qRT-PCR)检测35例肝癌组织及相应癌旁组织和10例正常肝组织中Claudin-1和Claudin-10mRNA的表达水平,同时用免疫组化SP(Streptavidin-perosidase)法技术检测35例肝癌组织及其相应癌旁组织中Claudin-1和Claudin-10蛋白的表达情况。
结果:Claudin-1 mRNA在肝癌组织中的表达明显低于癌旁组织及正常肝组织,差异有统计学意义(P<0.05);而癌旁组织与正常肝组织比较,差异无统计学意义(P>0.05);Claudin-1 mRNA的表达与HCC患者性别、年龄、AFP表达水平、HBsAg、病理分化程度、包膜完整性、门静脉癌栓形成、肿瘤个数及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05)。HCC组织及癌旁组织中均有Claudin-1蛋白表达,其阳性表达率分别为65.7%和88.6%。Claudin-1蛋白表达于阳性细胞胞质及胞膜上;Claudin-1蛋白在HCC组织中的表达显著低于癌旁组织(P<0.05);Claudin-1蛋白表达与HCC患者性别、年龄、肿瘤个数、AFP表达水平、HBsAg、包膜完整性及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05);而与肝癌病理分化程度及门脉癌栓形成相关(P<0.05)。Claudin-10 mRNA在肝癌组织中的表达明显高于癌旁组织及正常肝组织,差异有统计学意义(P<0.05);而癌旁组织与正常肝组织比较,差异无统计学意义(P>0.05);Claudin-10 mRNA的表达与HCC患者性别、年龄、AFP表达水平、HBsAg、病理分化程度、包膜完整性、门静脉癌栓形成、肿瘤个数及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05)。HCC组织及癌旁组织中均有Claudin-10蛋白表达,其阳性表达率分别为60%和22.9%。Claudin-10蛋白表达于阳性细胞胞质及胞膜上;Claudin-10蛋白在HCC组织中的表达显著高于癌旁组织(P<0.05);Claudin-10蛋白表达与HCC患者性别、年龄、肿瘤个数、AFP表达水平、HBsAg、包膜完整性及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05);而与肝癌病理分化程度及门脉癌栓形成相关(P<0.05)。
结论:Claudin-1和Claudin-10与HCC的发生、浸润和转移有关;Claudin-1和Claudin-10可作为HCC发生、发展的预测指标之一。
Objective: To detect the expression of Claudin-1and Claudin-10 in the HCC tissues ,paracarcinomatous tissues and normal liver tissues and explore their relationships with the oncogenesis and prognosis of HCC.
Methods: Fluorescence and real-time quantitative PCR were carried out to detect the level of Claudin-1and Claudin-10 mRNA from 35 hepatocellar carcinoma tissues and their corresponding normal tissues and 10 normal liver tissues,and the expression of Claudin-1 and Claudin-10 protein were detected by immunohistochemical SP method in 35 hepatocellar carcinoma tissues and their corresponding normal tissues.
Results: Lower expression of Claudin-1 mRNA was found in hepatocellar carcinoma tissues,compared with that in their corresponding normal tissues (P<0.05),but not between paracarcinomatous tissues and normal liver tissues (P>0.05). The level of Claudin-1mRNA expression in hepatocellar carcinoma was not significantly correlated with sex,age,AFP levels,HBsAg,pathological types, the integrity of tumor capsule,Portal vein tumor thrombus,tumor number and tumor size (P>0.05).and the expression of Claudin-1 mRNA in HCC tissues has no correlation with the One-year disease-free survival of patients (P>0.05). The expression of Claudin-1 protein was observed in HCC tissues and paracarcinomatous tissues,The positive rate of Claudin-1 protein were 65.7%,88.6%respectively. The brown granules of positive cell were mainly distributed in the cytoplasm and cell membrane. The expression of Claudin-1 protein in HCC tissues was significantly lower than that in the paracarcinomatous tissues (P<0.05). Claudin-1 protein expression were not related to sex,age,tumor number,AFP levels,HBsAg,the integrity of tumor capsule and tumor size (P>0.05),and has no correlation with the One-year disease-free survival of patients (P>0.05). But were significantly correlated with pathological differentiation of HCC,Portal vein tumor thrombus (P<0.05).Higher expression of Claudin-10 mRNA was found in hepatocellar carcinoma tissues,compared with that in their corresponding normal tissues (P<0.05),but not between paracarcinomatous tissues and normal liver tissues (P>0.05).The level of Claudin-10 mRNA expression in hepatocellar carcinoma was not significantly correlated with sex,age,AFP levels,HBsAg,pathological types,the integrity of tumor capsule,portal vein tumor thrombus,tumor number and tumor size (P>0.05). and the expression of Claudin-10 mRNA in HCC tissues has no correlation with the One-year disease-free survival of patients (P>0.05). The expression of Claudin-10 protein was observed in HCC tissues and paracarcinomatous tissues,the positive rate of Claudin-10 protein were 60%,22.9%respectively. The brown granules of positive cell were mainly distributed in the cytoplasm and cell membrane. The expression of Claudin-10 protein in HCC tissues was significantly higher than that in the paracarcinomatous tissues (P<0.05). Claudin-1 protein expression were not related to sex,age,tumor number,AFP levels,HBsAg,the integrity of tumor capsule and tumor size (P>0.05),and has no correlation with the One-year disease-free survival of patients (P>0.05). But were significantly correlated with pathological differentiation of HCC,portal vein tumor thrombus (P<0.05).
Conclusion: Claudin-1and Claudin-10 are related to the carcinogenesis,infiltration and metastasis of HCC,the level of Claudin-1and Claudin-10 expression might be a valuable marker for diagnosis and prognosis of HCC.
方法:采用实时荧光定量PCR(qRT-PCR)检测35例肝癌组织及相应癌旁组织和10例正常肝组织中Claudin-1和Claudin-10mRNA的表达水平,同时用免疫组化SP(Streptavidin-perosidase)法技术检测35例肝癌组织及其相应癌旁组织中Claudin-1和Claudin-10蛋白的表达情况。
结果:Claudin-1 mRNA在肝癌组织中的表达明显低于癌旁组织及正常肝组织,差异有统计学意义(P<0.05);而癌旁组织与正常肝组织比较,差异无统计学意义(P>0.05);Claudin-1 mRNA的表达与HCC患者性别、年龄、AFP表达水平、HBsAg、病理分化程度、包膜完整性、门静脉癌栓形成、肿瘤个数及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05)。HCC组织及癌旁组织中均有Claudin-1蛋白表达,其阳性表达率分别为65.7%和88.6%。Claudin-1蛋白表达于阳性细胞胞质及胞膜上;Claudin-1蛋白在HCC组织中的表达显著低于癌旁组织(P<0.05);Claudin-1蛋白表达与HCC患者性别、年龄、肿瘤个数、AFP表达水平、HBsAg、包膜完整性及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05);而与肝癌病理分化程度及门脉癌栓形成相关(P<0.05)。Claudin-10 mRNA在肝癌组织中的表达明显高于癌旁组织及正常肝组织,差异有统计学意义(P<0.05);而癌旁组织与正常肝组织比较,差异无统计学意义(P>0.05);Claudin-10 mRNA的表达与HCC患者性别、年龄、AFP表达水平、HBsAg、病理分化程度、包膜完整性、门静脉癌栓形成、肿瘤个数及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05)。HCC组织及癌旁组织中均有Claudin-10蛋白表达,其阳性表达率分别为60%和22.9%。Claudin-10蛋白表达于阳性细胞胞质及胞膜上;Claudin-10蛋白在HCC组织中的表达显著高于癌旁组织(P<0.05);Claudin-10蛋白表达与HCC患者性别、年龄、肿瘤个数、AFP表达水平、HBsAg、包膜完整性及肿瘤大小无关(P>0.05),与患者术后一年无瘤生存率无关(P>0.05);而与肝癌病理分化程度及门脉癌栓形成相关(P<0.05)。
结论:Claudin-1和Claudin-10与HCC的发生、浸润和转移有关;Claudin-1和Claudin-10可作为HCC发生、发展的预测指标之一。
Objective: To detect the expression of Claudin-1and Claudin-10 in the HCC tissues ,paracarcinomatous tissues and normal liver tissues and explore their relationships with the oncogenesis and prognosis of HCC.
Methods: Fluorescence and real-time quantitative PCR were carried out to detect the level of Claudin-1and Claudin-10 mRNA from 35 hepatocellar carcinoma tissues and their corresponding normal tissues and 10 normal liver tissues,and the expression of Claudin-1 and Claudin-10 protein were detected by immunohistochemical SP method in 35 hepatocellar carcinoma tissues and their corresponding normal tissues.
Results: Lower expression of Claudin-1 mRNA was found in hepatocellar carcinoma tissues,compared with that in their corresponding normal tissues (P<0.05),but not between paracarcinomatous tissues and normal liver tissues (P>0.05). The level of Claudin-1mRNA expression in hepatocellar carcinoma was not significantly correlated with sex,age,AFP levels,HBsAg,pathological types, the integrity of tumor capsule,Portal vein tumor thrombus,tumor number and tumor size (P>0.05).and the expression of Claudin-1 mRNA in HCC tissues has no correlation with the One-year disease-free survival of patients (P>0.05). The expression of Claudin-1 protein was observed in HCC tissues and paracarcinomatous tissues,The positive rate of Claudin-1 protein were 65.7%,88.6%respectively. The brown granules of positive cell were mainly distributed in the cytoplasm and cell membrane. The expression of Claudin-1 protein in HCC tissues was significantly lower than that in the paracarcinomatous tissues (P<0.05). Claudin-1 protein expression were not related to sex,age,tumor number,AFP levels,HBsAg,the integrity of tumor capsule and tumor size (P>0.05),and has no correlation with the One-year disease-free survival of patients (P>0.05). But were significantly correlated with pathological differentiation of HCC,Portal vein tumor thrombus (P<0.05).Higher expression of Claudin-10 mRNA was found in hepatocellar carcinoma tissues,compared with that in their corresponding normal tissues (P<0.05),but not between paracarcinomatous tissues and normal liver tissues (P>0.05).The level of Claudin-10 mRNA expression in hepatocellar carcinoma was not significantly correlated with sex,age,AFP levels,HBsAg,pathological types,the integrity of tumor capsule,portal vein tumor thrombus,tumor number and tumor size (P>0.05). and the expression of Claudin-10 mRNA in HCC tissues has no correlation with the One-year disease-free survival of patients (P>0.05). The expression of Claudin-10 protein was observed in HCC tissues and paracarcinomatous tissues,the positive rate of Claudin-10 protein were 60%,22.9%respectively. The brown granules of positive cell were mainly distributed in the cytoplasm and cell membrane. The expression of Claudin-10 protein in HCC tissues was significantly higher than that in the paracarcinomatous tissues (P<0.05). Claudin-1 protein expression were not related to sex,age,tumor number,AFP levels,HBsAg,the integrity of tumor capsule and tumor size (P>0.05),and has no correlation with the One-year disease-free survival of patients (P>0.05). But were significantly correlated with pathological differentiation of HCC,portal vein tumor thrombus (P<0.05).
Conclusion: Claudin-1and Claudin-10 are related to the carcinogenesis,infiltration and metastasis of HCC,the level of Claudin-1and Claudin-10 expression might be a valuable marker for diagnosis and prognosis of HCC.
引文
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1. Furuse M,Fujita K,Hiiragi T,et al. Claudin-1and-2:novel integral membrane proteins localizing at tight junctions with cell to cell contact and the extracellular matrix no sequence similarity to occluding[J]. Cell Biol,1998,141(8):1539-1550.
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4. Piehl C,Piontek J,Cording J, et al. Participation of the second extracellular loop of Claudin-5 in paracellular tightening against ions,small and large molecules[J]. Cell Mol Life Sci,2010,67(12):2131-2140.
5. Krause G , Winkler L , Mueller SL , et a1. Structure and function of clandins[J].Bioehim Biophys Acta,2008,1778(3):631-645.
6. Piontek J,Winkler L,Wolburg H,et a1.Formation of tight junction:determinants of homophilic interaction between classic Claudin.FASEB J,2008.22:146-158.
7. Yoon CH,Kim MJ,Park MJ,et al. Claudin-1 acts through c-abl-protein kinase C(PKC) signaling and has a causal role in the acquisition of invasive capacity in human liver cells[J]. Jour Biol Chem,2010,285(1):226-233.
8.雷军,夏祥国.紧密连接蛋白claudin的研究进展[J].泸州医学院学报,2009,32(6):655-657.
9. Ishida M , Kushjma R , Okabe H , et al. Claudin expression in rectal well-differentiated endocrine neoplasms(carcinoid tumors)[J]. Oncol Rep,2009,21(1):113-117.
10. Fritzsche FR,Oelrich B,Johannsen M,et al. Claudin-1 protein expression is a prognostic marker of patient survival in renal cell carcinomas[J]. Clin Cancer Res,2008,14(21):7035-7042.
11. Chao YC,Pan SH,Yang SC,et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma[J]. Am J Respir Crit Care Med,2009,179(2):123-133.
12. Soini Y. Expression of Claudin-1,-2,-3,-4,-5 and -7 in various types of tumors[J]. Histopathology,2005;46(5):551-560.
13. Sung CO,Han SY,Kim SH,et al. Low expression of Claudin-4 is associated with poor prognosis in esophageal squamous cell carcinoma[J]. Ann Surg Oncol,2011,18(1):273-281.
14. Kominsky SL,Argani P,Korz D,et al. Loss of the tight junction protein Claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast[J]. Oncogene,2003,22(13):2021-2033.
15. Katoh M. CLDN23 gene,frequently downregulated in intestinaltype gastric cancer,is a nove member of CLAUDIN gene family[J]. Int J Med,2003,11(6):683-689.
16. Nemeth J,Nemeth Z,Tatrai P,et al. High expression of Claudin-1 protein in papillary thyroid tumor and its regional lympa node metastasis[J]. Pathol Oncol Res,2010,16(1):19-27.
17. 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):7878-7881.
18. Landers KA,Samaratunga H,Teng L,et al. Identification of Claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer[J]. Br J Cancer,2008,99(3):491-501.
19. Montgonmery E,Mamelak AJ,Gibson M,et al. Overexpression of Claudin proteins in esophageal adencarcinoma and its precursor lesions[J]. Appl Immunohistochem Mol Morphol,2006,14(1):24-30.
20. Resinck MB,Gavilanez M,Newton E,et al. Claudin expression gastric adenoeareinomas:a tissue micmarray study with prognostic correlation[J]. Hum Pathol,2005,36(8):886-892.
21. De Oliveriraa SS,De Oliveira IM,De Souza W,et al. Claudin upregulation in human colorectal cancer[J]. Febs Lett,2005,579(27):6179-6185.
22. Nichols LS,Ashfaq R,Iacobuzio-Donahue CA,et al. Claudin-4 protein expressions in primary and metastatic pancreatic cancer:support for use as a therapeutic target[J]. Am J Clin Pathol,2004,121(3):226-230.
23. Agarwal R,D Souza T,Morin PJ. Claudin-3 and Claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity[J]. Cancer Res,2005,65(16):7378-7385.
24. Cheung ST,Leung KL,Ip YC,et al . Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma[J]. Clin Cancer Res,2005,11(2Pt1):551-556.
25. Michl P,Barth C,Buchholz M,et al. Claudin-4 expression deceases invasiveness and metastatic potential of pancreatic cancer[J]. Cancer Res,2003,63(19):6265-6271.
26.陈徐银,郑树森. Claudin蛋白与恶性肿瘤关系的研究进展[J].国际外科学杂志,2006,33(5):380-383.
27.雷军,夏祥国.紧密连接蛋白Claudin的研究进展[J].泸州医学院学报,2009,32(6):655-657.
28.王刚,吴小侯. Claudin-3在膀胱移行细胞癌中的表达及意义[J].重庆医学,2009,38(17):2154-2158.
29. Hoevel T,Macek R,Swisshelm K,et al. Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids[J]. Int J Cancer,2004,108(3):374-383.
30. Yamauchi K,Rai T,Kobayashi K,et al. Disease-causing mutant WNK4 increase paracellular chloride permeability and phosphorylates Claudin[J]. ProcNatl Acad Sci USA,2004,101(13):4690-4694.
31.李家兵,李锦秀,姚惠. Claudin-3 mRNA在前列腺癌组织中的表达及意义[J].川北医学院学报,2009,24(3):238-240.
32. Dhawan P,Singh AB,Deane NG,et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer[J]. J Clin Invest,2005,115(7):17652-17656.
33. Karanjawala Z,Illei PB,Ashfaq R,et al. New markers of pancreatic cancer identified through differential gene expression ana1yses:Claudin 18 and annexin A8[J].Am J Surg Pathol,2008,32(2):188-196.
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19. Kominsky SL,Argani P,Korz D,et al. Loss of the tight junction protein Claudin-7 correlates with histological grade in both ductal carcinoma in situand invasive ductal carcinoma of the breast[J]. Oncogene,2003,22(13):2021-2033.
20. Katoh M. CLDN23 gene,frequently downregulated in intestinaltype gastric cancer,is a nove member of CLAUDIN gene family[J]. Int J Med,2003,11(6):683-689.
21. Nemeth J,Nemeth Z,Tatrai P,et al. High expression of Claudin-1 protein in papillary thyroid tumor and its regional lympa node metastasis[J]. Pathol Oncol Res,2010,16(1):19-27.
22. 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):7878-7881.
23. Landers KA,Samaratunga H,Teng L,et al. Identification of Claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer[J]. Br J Cancer,2008,99(3):491-501.
24. Montgonmery E,Mamelak AJ,Gibson M,et al. Overexpression of Claudin proteins in esophageal adencarcinoma and its precursor lesions[J]. Appl Immunohistochem Mol Morphol,2006,14(1):24-30.
25. Resinck MB,Gavilanez M,Newton E,et al. Claudin expression gastric adenoeareinomas:a tissue micmarray study with prognostic correlation[J]. Hum Pathol,2005,36(8):886-892.
26. De Oliveriraa SS,De Oliveira IM,De Souza W,et al. Claudin upregulation in human colorectal cancer[J]. Febs Lett,2005,579(27):6179-6185.
27. Nichols LS,Ashfaq R,Iacobuzio-Donahue CA. et al. Claudin-4 protein expressions in primary and metastatic pancreatic cancer:support for use as a therapeutic target[J]. Am J Clin Pathol,2004,121(3):226-230.
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29.雷军,夏祥国.紧密连接蛋白Claudin的研究进展[J].泸州医学院学报,2009,32(6):655-657.
30. Karanjawala Z,Illei PB,Ashfaq R,et al. New markers of pancreatic cancer identified through differential gene expression ana1yses:Claudin 18 and annexin A8[J].Am J Surg Pathol,2008,32(2):188-196.
31. Nishino R,Honda M,Yamashita T,et al. Identification of novel candidate tumour marker genes for intrahepatic cholangiocarcinoma[J]. J Hepatol,2008,49(2):207-216.
32. Michl P,Gress TM.Bacteria and bacterial toxins as therapeutic agents for solid tumors[J].Curt Cancer Drug Targets,2004,4(8):689-702.
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39. Fritzsche FR,Oelrich B,Johannsen M,et al. Claudin-1 protein expression isa prognostic marker of patient survival in renal cell carcinomas[J]. Clin Cancer Res,2008,14(21):7035-7042.
40. Chao YC,Pan SH,Yang SC,et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma[J]. Am J Respir Crit Care Med,2009,179(2):123-133.
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49. Hoevel T,Macek R,Swisshelm K,et al. Reexpression of the TJ proteinCLDN1 induces apoptosis in breast tumor spheroids[J]. Int J Cancer,2004,108(3):374-383.
50. Yamauchi K,Rai T,Kobayashi K,et al. Disease-causing mutant WNK4 increase paracellular chloride permeability and phosphorylates Claudin[J]. Proc Natl Acad Sci USA,2004,101(13):4690-4694.
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54. Agarwal R,D Souza T,Morin PJ. Claudin-3 and Claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity[J]. Cancer Res,2005,65(16):7378-7385.
55. Dhawan P,Singh AB,Deane NG,et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer[J]. J Clin Invest,2005,115(7):17652-17656.
56. Ip YC,Cheung ST,Lee YT,et al. Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells[J]. Mol Cancer Ther 2007,6(11):2858-2867.
1. Furuse M,Fujita K,Hiiragi T,et al. Claudin-1and-2:novel integral membrane proteins localizing at tight junctions with cell to cell contact and the extracellular matrix no sequence similarity to occluding[J]. Cell Biol,1998,141(8):1539-1550.
2. Morin P J. Claudin proteins in human cancer:promising new targets for diagnosis and therapy [J]. Cancer Res,2005,65(21):9603-9606.
3. Hewitt KJ,Agarwal R,Morin PJ.The claudin gene family:expression in norm al and neoplastic tissues[J]. BMC Canccr,2006,6(11):186-189.
4. Piehl C,Piontek J,Cording J, et al. Participation of the second extracellular loop of Claudin-5 in paracellular tightening against ions,small and large molecules[J]. Cell Mol Life Sci,2010,67(12):2131-2140.
5. Krause G , Winkler L , Mueller SL , et a1. Structure and function of clandins[J].Bioehim Biophys Acta,2008,1778(3):631-645.
6. Piontek J,Winkler L,Wolburg H,et a1.Formation of tight junction:determinants of homophilic interaction between classic Claudin.FASEB J,2008.22:146-158.
7. Yoon CH,Kim MJ,Park MJ,et al. Claudin-1 acts through c-abl-protein kinase C(PKC) signaling and has a causal role in the acquisition of invasive capacity in human liver cells[J]. Jour Biol Chem,2010,285(1):226-233.
8.雷军,夏祥国.紧密连接蛋白claudin的研究进展[J].泸州医学院学报,2009,32(6):655-657.
9. Ishida M , Kushjma R , Okabe H , et al. Claudin expression in rectal well-differentiated endocrine neoplasms(carcinoid tumors)[J]. Oncol Rep,2009,21(1):113-117.
10. Fritzsche FR,Oelrich B,Johannsen M,et al. Claudin-1 protein expression is a prognostic marker of patient survival in renal cell carcinomas[J]. Clin Cancer Res,2008,14(21):7035-7042.
11. Chao YC,Pan SH,Yang SC,et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma[J]. Am J Respir Crit Care Med,2009,179(2):123-133.
12. Soini Y. Expression of Claudin-1,-2,-3,-4,-5 and -7 in various types of tumors[J]. Histopathology,2005;46(5):551-560.
13. Sung CO,Han SY,Kim SH,et al. Low expression of Claudin-4 is associated with poor prognosis in esophageal squamous cell carcinoma[J]. Ann Surg Oncol,2011,18(1):273-281.
14. Kominsky SL,Argani P,Korz D,et al. Loss of the tight junction protein Claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast[J]. Oncogene,2003,22(13):2021-2033.
15. Katoh M. CLDN23 gene,frequently downregulated in intestinaltype gastric cancer,is a nove member of CLAUDIN gene family[J]. Int J Med,2003,11(6):683-689.
16. Nemeth J,Nemeth Z,Tatrai P,et al. High expression of Claudin-1 protein in papillary thyroid tumor and its regional lympa node metastasis[J]. Pathol Oncol Res,2010,16(1):19-27.
17. 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):7878-7881.
18. Landers KA,Samaratunga H,Teng L,et al. Identification of Claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer[J]. Br J Cancer,2008,99(3):491-501.
19. Montgonmery E,Mamelak AJ,Gibson M,et al. Overexpression of Claudin proteins in esophageal adencarcinoma and its precursor lesions[J]. Appl Immunohistochem Mol Morphol,2006,14(1):24-30.
20. Resinck MB,Gavilanez M,Newton E,et al. Claudin expression gastric adenoeareinomas:a tissue micmarray study with prognostic correlation[J]. Hum Pathol,2005,36(8):886-892.
21. De Oliveriraa SS,De Oliveira IM,De Souza W,et al. Claudin upregulation in human colorectal cancer[J]. Febs Lett,2005,579(27):6179-6185.
22. Nichols LS,Ashfaq R,Iacobuzio-Donahue CA,et al. Claudin-4 protein expressions in primary and metastatic pancreatic cancer:support for use as a therapeutic target[J]. Am J Clin Pathol,2004,121(3):226-230.
23. Agarwal R,D Souza T,Morin PJ. Claudin-3 and Claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity[J]. Cancer Res,2005,65(16):7378-7385.
24. Cheung ST,Leung KL,Ip YC,et al . Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma[J]. Clin Cancer Res,2005,11(2Pt1):551-556.
25. Michl P,Barth C,Buchholz M,et al. Claudin-4 expression deceases invasiveness and metastatic potential of pancreatic cancer[J]. Cancer Res,2003,63(19):6265-6271.
26.陈徐银,郑树森. Claudin蛋白与恶性肿瘤关系的研究进展[J].国际外科学杂志,2006,33(5):380-383.
27.雷军,夏祥国.紧密连接蛋白Claudin的研究进展[J].泸州医学院学报,2009,32(6):655-657.
28.王刚,吴小侯. Claudin-3在膀胱移行细胞癌中的表达及意义[J].重庆医学,2009,38(17):2154-2158.
29. Hoevel T,Macek R,Swisshelm K,et al. Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids[J]. Int J Cancer,2004,108(3):374-383.
30. Yamauchi K,Rai T,Kobayashi K,et al. Disease-causing mutant WNK4 increase paracellular chloride permeability and phosphorylates Claudin[J]. ProcNatl Acad Sci USA,2004,101(13):4690-4694.
31.李家兵,李锦秀,姚惠. Claudin-3 mRNA在前列腺癌组织中的表达及意义[J].川北医学院学报,2009,24(3):238-240.
32. Dhawan P,Singh AB,Deane NG,et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer[J]. J Clin Invest,2005,115(7):17652-17656.
33. Karanjawala Z,Illei PB,Ashfaq R,et al. New markers of pancreatic cancer identified through differential gene expression ana1yses:Claudin 18 and annexin A8[J].Am J Surg Pathol,2008,32(2):188-196.
34. Nishino R,Honda M,Yamashita T,et al. Identification of novel candidate tumour marker genes for intrahepatic cholangiocarcinoma[J]. J Hepatol,2008,49(2):207-216.
35. Michl P.Gress TM.Bacteria and bacterial toxins as therapeutic agents for solid tumors[J].Curt Cancer Drug Targets,2004,4(8):689-702.
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