胆管细胞癌组织JAG1基因及其蛋白表达水平与患者预后的关系

doi:10.3969/j.issn.1672-5069.2017.06.024

摘要/Abstract

摘要： 目的探讨JAG1蛋白表达水平对胆管细胞癌患者肿瘤切除术后预后的判断价值。方法2010年1月~2014年12月我院诊治的胆管细胞癌患者60例和良性胆道疾病患者60例。检测胆管细胞癌组织、癌旁组织和肝组织JAG1 mRNA及其蛋白表达,测定胆管癌患者术后血清JAG1水平。应用单因素和多因素非条件Logistic回归分析胆管癌患者手术后预后的危险因素。结果癌旁组织、肝组织、胆管癌组织JAG1蛋白阳性率分别为45.0%（27/60）、56.7%（34/60）和81.7%（49/60）,组间差异有统计学意义（P<0.05）;三种组织JAG1 mRNA水平和蛋白相对表达量分别为（0.91±0.34）和（0.57±0.15）、（1.15±0.48）和（0.84±0.47）、（1.96±0.58）和（1.64±0.58）,组间差异有统计学意义（P<0.05）;胆管癌患者血清JAG1水平为（205.35±22.51）pg/ml,显著高于良性胆道疾病患者【（102.56±16.52）pg/ml,P<0.05】;肝内胆管癌患者血清JAG1水平与CA125（r=0.41,P<0.05）、CEA（r=0.0.27,P<0.05）、CRP（r=0.17,P<0.05）、肿瘤浸润深度（r=0.13,P<0.05）、淋巴结转移（r=0.08,P<0.05）、TNM分期（r=0.14,P<0.05）、肿瘤分化程度（r=0.15,P<0.05）呈正相关;多因素Cox 比例风险回归模型分析显示,肿瘤浸润深度、淋巴结转移、TNM分期、分化程度、血清JAG1高水平是影响胆管癌患者无复发生存时间的危险因素（P<0.05）,肿瘤浸润深度、淋巴结转移、TNM分期、血清JAG1高水平是影响胆管癌患者总生存时间的危险因素（P<0.05）。结论JAG1蛋白可以作为胆管细胞癌患者肿瘤切除术后的预后指标,血清JAG1水平高患者术后预后差。

关键词: 胆管细胞癌, JAG1蛋白, 预后

Abstract: Objective To investigate the JAG1 protein expression on the prognosis of patients with intrahepatic cholangiocellular carcinoma （CCC）. Methods 60 patients with intrahepatic cholangiocarcinoma in our hospital between Jan 2010 and Dec 2014 were included and 60 patients with benign biliary diseases who were treated in our hospital during the same period were selected as control. JAG1 mRNA and its protein in liver tissues were detected. Serum JAG1 level was also measured by ELISA. Laboratory and clinical pathological parameters were recorded and the correlations of them to JAG1 were calculated. Univariate and multivariate unconditional Logistic regression analysis of risk factors for postoperative prognosis in patients with CCC was conducted. Results In paracancerous tissues,liver tissues and cholangiocarcinoma tissues,the positive expression rates of JAG1 protein were 45.0%（27/60）,56.7%（34/60）and 81.7%（49/60）,respectively,and the relative levels of JAG1 mRNA were （0.91±0.34） and （0.57±0.15）,（1.15±0.48） and （0.84±0.47）,（1.96±0.58） and （1.64±0.58）,respectively,（P<0.05）;serum JAG1 level in patients with CCC was（205.35±22.51）pg/ml,significantly higher than that in the controls[（102.56±16.52）pg/ml,P<0.05];serum JAG1 level in patients with intrahepatic CCC was positively correlated with CA125（r=0.41,P<0.05）,CEA（r=0.0.27,P<0.05）,CRP（r=0.17,P<0.05）,tumor invasion depth（r=0.13,P<0.05）,lymph node metastasis（r=0.08,P<0.05）,TNM stage（r=0.14,P<0.05） and tumor differentiation（r=0.15,P<0.05）;multivariate Cox proportional hazard regression model analysis showed that the depth of tumor invasion,lymph node metastasis,TNM staging,differentiation,high serum JAG1 level were the risk factors of relapse free survival （RFS） in patients with bile duct carcinoma（P<0.05）;the depth of tumor

牛福勇, 李福荣. 胆管细胞癌组织JAG1基因及其蛋白表达水平与患者预后的关系[J]. 实用肝脏病杂志, 2017, 20(6): 736-739.

Niu Fuyong, Li Furong. JAG1 protein expression on prognosis of patients with cholangiocellular carcinome after surgical resection[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2017, 20(6): 736-739.

参考文献

[1] Spolverato G,Kim Y,Alexandrescu S,et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcin-
oma following previous curative-intent surgical resection. Ann Surg Oncol,2016,23（1）:1-9.
[2] Kang SI,Kang J,Park HS,et al. Metastatic cholangiocarcinoma as a cause of appendicitis:a case report and literature review. J Hepatobiliary Pancreat Surg,2014,18（2）:60-63.
[3] Lee SW,Lee IS,Yu KC,et al. A case of mixed adenoneuroendocrine carcinoma of the common bile duct:Initially diagnosed as cholangiocarcinoma. Kor J Pathol,2014,48（6）:445-448.
[4] Lange S,Lampe J,Bossow S,et al. A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma. Hum Gene Ther,2013,24（5）:554-564.
[5] Patel T. New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol Hepatol,2014,49（2）:165-172.
[6] Frampton G,Coufal M,Li H,et al. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling. Exp Cell Res,2010,316（9）:1465-1478.
[7] Leong KG,Niessen K,Kulic I,et al. Jagged 1-mediated Notch activation induces epithelial-to-mesenchymal transition through slug-induced repression of E-cadherin. J Exp Med,2011,204（12）:2935-2948.
[8] Masakazu S,Eiji O,Yu N,et al. High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer. Cancer Sci,2016,107（11）:1705-1716.
[9] Katoh M. Notch ligand,JAG1 is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med,2006,17（4）:681-685.
[10] 刘兆国,朱智杰,周梁,等. Notch信号通路与肿瘤研究. 中国药理学通报,2012,28（8）:1045-1048.
[11] 欧阳合意,张艳丽,陈小伍,等. 肝癌组织DLK1和Jagged1表达临床意义探讨. 中华肿瘤防治杂志,2015,22（8）:610-613.
[12] 康凯夫,张艳丽,欧阳合意. 肝癌组织ABCG2和Jagged1表达临床意义的探讨. 中华肿瘤防治杂志,2013,20（6）:453-457.
[13] 刘虹,李建. Notch1受体和配体分子Jagged1蛋白在肝癌组织中的表达及意义. 中国现代医学杂志,2012,22（10）:45-48.
[14] Che L,Fan B, Pilo MG,et al. Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans. Oncogenesis,2016,73（5）:256-265.
[15] 曹玉文,杜小明,李文琴,等. Jagged-1基因在乳腺癌和正常乳腺组织中的表达及临床意义. 中国妇幼保健,2014,29（34）:5661-5663.
[16] 张秀青,李万胜,沈素朋,等. 卵巢上皮性癌中Notch-1和Jagged-1的表达及临床意义. 现代肿瘤医学,2015,21（7）:977-980.
[17] 王连东,孔亮,邓玉,等. 胃腺癌组织Notch1和Jagged1蛋白表达临床意义分析. 中华肿瘤防治杂志,2013,20（21）:1661-1664.
[18] Dickson BC,Mulligan AM,Zhang H,et al. High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Modern Pathol,2007,20（6）:685-693.
[19] Che L,Fan B,Pilo MG,et al. Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans. Oncogenesis,2016,73（5）:274-281.
[20] Hofmann JJ,Zovein AC,Koh H,et al. Jagged 1 in the portal vein mesenchyme regulates intrahepatic bile duct development:insights into Alagille syndrome.Development,2010,137（23）:4061-4072.