肝门部胆管腺癌组织TGR5表达变化与上皮间质转化和患者预后的关系
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摘要
目的观察肝门部胆管腺癌G蛋白偶联胆汁酸受体5(TGR5)表达变化,并分析其表达变化与肿瘤进展和患者预后的关系。方法选择肝门部胆管腺癌患者59例,取手术切除的胆管癌组织及其癌旁组织,采用免疫组化法检测TGR5、上皮间质转化(EMT)相关标志物[上皮细胞标志物E-钙黏蛋白(E-cadherin)、细胞角蛋白19(CK19),间质细胞标志物N-钙黏蛋白(N-cadherin)、波形蛋白(Vimentin)]及锌指结构转录因子1(ZEB1)蛋白表达。分析胆管癌组织TGR5表达与EMT相关标志物及ZEB1蛋白表达的关系,以及与患者临床病理特征和预后的关系。结果胆管癌组织TGR5表达明显高于癌旁组织,且其上皮细胞标志物E-cadherin、CK19表达明显低于癌旁组织,间质细胞标志物N-cadherin、Vimentin及ZEB1蛋白表达明显高于癌旁组织(P均<0.05)。胆管癌组织TGR5表达与E-cadherin、CK19表达均呈负相关关系(r分别为-0.718、-0.774,P均<0.05),与Vimentin、N-cadherin、ZEB1蛋白表达均呈正相关关系(r分别为0.763、0.817、0.698,P均<0.05)。胆管癌组织TGR5表达与肿瘤组织分化程度、淋巴结转移、神经受累有关(P均<0.05),与患者性别、年龄无关(P均>0.05)。以胆管癌组织TGR5相对表达量的平均值为临界值,将患者分为TGR5高表达者30例与低表达者29例。TGR5高表达者术后无瘤生存时间、总生存时间均明显低于TGR5低表达者(P均<0.05)。结论肝门部胆管腺癌组织TGR5高表达,其高表达与肿瘤侵袭和转移以及患者不良预后有关。
Objective To observe the expression changes of Takeda G-protein receptor 5(TGR5) in patients with hilar cholangiocarcinoma and to analyze its relationships with tumor progression and prognosis. Methods The cholangiocarcinoma tissues and adjacent tissues were obtained from 59 patients with hilar cholangiocarcinoma to detect the expression of TGR5, epithelial-mesenchymal transition(EMT)-related markers [epithelial cell markers E-cadherin and cytokeratin 19(CK19), mesenchymal cell markers N-cadherin, and Vimentin] and the Zinc finger E-box-binding homeobox 1(ZEB1) by using immunohistochemical method. We analyzed the correlation between TGR5 expression in cholangiocarcinoma tissues, EMT-related markers and ZEB1 expression, meanwhile, the relationships between TGR5 expression and patients′ clinicopathological parameters and prognosis were analyzed. Results The expression of TGR5 in the cholangiocarcinoma tissues was significantly higher than that in the adjacent tissues, and the expression of epithelial cell makers, E-cadherin and CK19 was significantly lower than that in the adjacent tissues, while the expression of mesenchymal cell makers, N-cadherin, Vimentin and ZEB1 was significantly higher than that in the adjacent tissues(all P<0.05). TGR5 expression in the cholangiocarcinoma was negatively correlated with E-cadherin and CK19 expression, and was positively correlated with Vimentin, N-cadherin and ZEB1 expression(all P<0.05). TGR5 expression in the cholangiocarcinoma tissues was related to tumor differentiation, lymphatic metastasis and nerve involvement(all P<0.05), and was not related to gender or age(all P>0.05). The tumor-free survival time and total survival time of patients with high TGR5 expression were lower than those with low TGR5 expression(all P<0.05). Conclusion TGR5 is highly expressed in the hilar cholangiocarcinoma and is associated with tumor invasion, metastasis and poor prognosis.
Objective To observe the expression changes of Takeda G-protein receptor 5(TGR5) in patients with hilar cholangiocarcinoma and to analyze its relationships with tumor progression and prognosis. Methods The cholangiocarcinoma tissues and adjacent tissues were obtained from 59 patients with hilar cholangiocarcinoma to detect the expression of TGR5, epithelial-mesenchymal transition(EMT)-related markers [epithelial cell markers E-cadherin and cytokeratin 19(CK19), mesenchymal cell markers N-cadherin, and Vimentin] and the Zinc finger E-box-binding homeobox 1(ZEB1) by using immunohistochemical method. We analyzed the correlation between TGR5 expression in cholangiocarcinoma tissues, EMT-related markers and ZEB1 expression, meanwhile, the relationships between TGR5 expression and patients′ clinicopathological parameters and prognosis were analyzed. Results The expression of TGR5 in the cholangiocarcinoma tissues was significantly higher than that in the adjacent tissues, and the expression of epithelial cell makers, E-cadherin and CK19 was significantly lower than that in the adjacent tissues, while the expression of mesenchymal cell makers, N-cadherin, Vimentin and ZEB1 was significantly higher than that in the adjacent tissues(all P<0.05). TGR5 expression in the cholangiocarcinoma was negatively correlated with E-cadherin and CK19 expression, and was positively correlated with Vimentin, N-cadherin and ZEB1 expression(all P<0.05). TGR5 expression in the cholangiocarcinoma tissues was related to tumor differentiation, lymphatic metastasis and nerve involvement(all P<0.05), and was not related to gender or age(all P>0.05). The tumor-free survival time and total survival time of patients with high TGR5 expression were lower than those with low TGR5 expression(all P<0.05). Conclusion TGR5 is highly expressed in the hilar cholangiocarcinoma and is associated with tumor invasion, metastasis and poor prognosis.
引文
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[3] Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application[J]. Dig Liver Dis, 2014,46(4):302-312.
[4] Carino A, Graziosi L, D′Amore C, et al. The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines[J]. Oncotarget, 2016,7(38):61021-61035.
[5] Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma-evolving concepts and therapeutic strategies[J]. Nat Rev Clin Oncol, 2018,15(2):95-111.
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[7] Guo C, Chen WD, Wang YD. TGR5, not only a metabolic regulator[J]. Front Physiol, 2016,7:646.
[8] Vaquero J, Guedj N, Clapéron A, et al. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks[J]. J Hepatol, 2017,66(2):424-441.
[9] Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016[J]. Cell, 2016,166(1):21-45.
[10] 韩姣,曾凡军,陈世雄.上皮间质转化相关信号通路在肺纤维化发生发展中的作用[J].山东医药,2015,55(17):101-103.
[11] Wang W, Dong L, Zhao B, et al. Ecadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT[J]. Oncol Rep, 2018,40(3):1641-1649.
[12] Tanaka T, Goto K, Iino M. Sec8 modulates TGF-β induced EMT by controlling N-cadherin via regulation of Smad3/4[J]. Cell Signal, 2017,29:115-126.
[13] Kim YR, Park MK, Kang GJ, et al. Leukotriene B4 induces EMT and vimentin expression in PANC-1 pancreatic cancer cells: Involvement of BLT2 via ERK2 activation[J]. Prostaglandins Leukot Essent Fatty Acids, 2016,115:67-76.
[14] Huang D, Xu W, Xu X, et al. EMT influences the expression of CK19 in pleural effusion-derived lung cancer cells and their invasion and metastasis[J]. Oncol Lett, 2016,12(6):5052-5058.
[15] Liu X, Chen B, You W, et al. The membrane bile acid receptor TGR5 drives cell growth and migration via activation of the JAK2/STAT3 signaling pathway in non-small cell lung cancer[J]. Cancer Lett, 2018,412:194-207.
[16] Caramel J, Ligier M, Puisieux A. Pleiotropic roles for ZEB1 in cancer[J]. Cancer Res, 2018,78(1):30-35.
[17] Krebs AM, Mitschke J, Lasierra LM, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer[J]. Nat Cell Biol, 2017,19(5):518-529.
[18] Terashita K, Chuma M, Hatanaka Y, et al. ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma[J]. J Clin Pathol, 2016,69(7):593-599.
[19] Kong D, Liang J, Li R, et al. Prognostic significance of snail expression in hilar cholangiocarcinoma[J]. Braz J Med Biol Res, 2012,45(7):617-624.
[2] Deutschmann K, Reich M, Klindt C, et al. Bile acid receptors in the biliary tree: TGR5 in physiology and disease[J]. Biochim Biophys Acta Mol Basis Dis, 2018,1864(4 Pt B):1319-1325.
[3] Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application[J]. Dig Liver Dis, 2014,46(4):302-312.
[4] Carino A, Graziosi L, D′Amore C, et al. The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines[J]. Oncotarget, 2016,7(38):61021-61035.
[5] Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma-evolving concepts and therapeutic strategies[J]. Nat Rev Clin Oncol, 2018,15(2):95-111.
[6] Squadroni M, Tondulli L, Gatta G, et al. Cholangiocarcinoma[J]. Crit Rev Oncol Hematol, 2017,116:11-31.
[7] Guo C, Chen WD, Wang YD. TGR5, not only a metabolic regulator[J]. Front Physiol, 2016,7:646.
[8] Vaquero J, Guedj N, Clapéron A, et al. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks[J]. J Hepatol, 2017,66(2):424-441.
[9] Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016[J]. Cell, 2016,166(1):21-45.
[10] 韩姣,曾凡军,陈世雄.上皮间质转化相关信号通路在肺纤维化发生发展中的作用[J].山东医药,2015,55(17):101-103.
[11] Wang W, Dong L, Zhao B, et al. Ecadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT[J]. Oncol Rep, 2018,40(3):1641-1649.
[12] Tanaka T, Goto K, Iino M. Sec8 modulates TGF-β induced EMT by controlling N-cadherin via regulation of Smad3/4[J]. Cell Signal, 2017,29:115-126.
[13] Kim YR, Park MK, Kang GJ, et al. Leukotriene B4 induces EMT and vimentin expression in PANC-1 pancreatic cancer cells: Involvement of BLT2 via ERK2 activation[J]. Prostaglandins Leukot Essent Fatty Acids, 2016,115:67-76.
[14] Huang D, Xu W, Xu X, et al. EMT influences the expression of CK19 in pleural effusion-derived lung cancer cells and their invasion and metastasis[J]. Oncol Lett, 2016,12(6):5052-5058.
[15] Liu X, Chen B, You W, et al. The membrane bile acid receptor TGR5 drives cell growth and migration via activation of the JAK2/STAT3 signaling pathway in non-small cell lung cancer[J]. Cancer Lett, 2018,412:194-207.
[16] Caramel J, Ligier M, Puisieux A. Pleiotropic roles for ZEB1 in cancer[J]. Cancer Res, 2018,78(1):30-35.
[17] Krebs AM, Mitschke J, Lasierra LM, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer[J]. Nat Cell Biol, 2017,19(5):518-529.
[18] Terashita K, Chuma M, Hatanaka Y, et al. ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma[J]. J Clin Pathol, 2016,69(7):593-599.
[19] Kong D, Liang J, Li R, et al. Prognostic significance of snail expression in hilar cholangiocarcinoma[J]. Braz J Med Biol Res, 2012,45(7):617-624.
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