Yang Ming-Chen, Wang Chih-Jung, Liao Pao-Chi, Yen Chia-Jui, Shan Yan-Shen
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan, Taiwan, China.
Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan, Taiwan, China.
Am J Cancer Res. 2014 Nov 19;4(6):751-63. eCollection 2014.
Liver fibrosis is a risk factor for hepatoma. Activated hepatic stellate cells (HSCs) play a critical role in progression of hepatoma. Resected hepatoma patients with high α-SMA+HSCs infiltration had worse survival, OR: 2.2 and p=0.0434. We hypothesized that HSCs could increase the epithelial-mesenchymal transition (EMT) ability of hepatoma cells. In murine model of liver fibrosis with injection of ML1 mice HCC cell line, E-cadherin was lost at the margin of tumor nodule around α-SMA+HSC sites. In subcutaneous tumor model, HSCs could increase the metastatic nodules in the lung, and the expression of E-cadherin was decreased and the Slug was induced. To elucidate the effect of HSCs on hepatoma cells, HSC-T6 was co-cultured with ML1 and the condition medium of HSC-T6 can trigger ML1 cell morphological change, down-expression of E-cadherin, induction of Slug expression, and cell migration. Proteomic analysis of the condition medium showed that collagen I was the target molecule. Collagen type I alone also induced EMT of ML1 cells. Knockdown of collagen type I in HSC-T6 could decrease its induction of EMT on ML1 cells. In conclusion, HSC can secrete collagen type I to trigger hepatoma cells to undergo EMT for metastasis.
肝纤维化是肝癌的一个危险因素。活化的肝星状细胞（HSCs）在肝癌进展中起关键作用。α-SMA+HSCs浸润程度高的肝癌切除患者生存率较差，比值比（OR）为2.2，p = 0.0434。我们假设肝星状细胞可增强肝癌细胞的上皮-间质转化（EMT）能力。在注射ML1小鼠肝癌细胞系的肝纤维化小鼠模型中，肿瘤结节边缘α-SMA+HSC部位周围的E-钙黏蛋白缺失。在皮下肿瘤模型中，肝星状细胞可增加肺部转移结节，E-钙黏蛋白表达降低，且诱导了Slug的表达。为阐明肝星状细胞对肝癌细胞的作用，将HSC-T6与ML1共培养，HSC-T6的条件培养基可引发ML1细胞形态改变、E-钙黏蛋白表达下调、Slug表达诱导及细胞迁移。对条件培养基的蛋白质组分析表明，I型胶原是靶分子。单独的I型胶原也可诱导ML1细胞发生EMT。敲低HSC-T6中的I型胶原可降低其对ML1细胞EMT的诱导作用。总之，肝星状细胞可分泌I型胶原，触发肝癌细胞发生EMT以实现转移。
