初级胆汁酸促进肝癌细胞生长的作用及机制

Hepatocellular carcinoma is a malignant tumor common in China, and the underlying mechanism of its development is currently unclear. Previous studies indicated that increased levels of bile acids are closely associated with occurrence of liver cancer. Inspired by our research in gastric cancer, we found that a novel estrogen receptor isoform ER-α36 was highly expressed in human specimens of liver cancer, and was positively correlated with EGFR expression. Primary bile acids exhibited estrogen-like activities in established liver cancer cells. Both cholic acid and chenodesoxycholic acid increased the levels of ER-α36 and EGFR expression, up-regulated ERK phosphorylation and promoted liver cancer cell growth. In the liver cancer cells with knocked-down levels of ER-α36 expression, both cholic acid and chenodesoxycholic acid failed to promote cell growth. These results suggested that primary bile acids might promote growth of liver cancer cells through ER-α36 mediated signaling and the ER-α36-EGFR regulatory loop. Thus, we hypothesized that primary bile acids posses estrogen-like activities, and promote growth of liver cancer cells. In this proposed study, we will study the functions and underlying mechanisms of primary bile acid effects on the ER-α36 signaling and its regulatory loop with EGFR in liver cancer cell growth with experiments including human tissue staining, in vivo animal, in vitro cell/stem cell, protein and gene assays. These results are of great importance in clinical and biological research.

肝细胞癌是我国常见恶性肿瘤，其发生机制目前不清。有研究发现，高浓度初级胆汁酸与肝癌的发生存在关联。申请者受本实验室胃癌研究的启发，在人肝细胞癌组织中发现新型雌激素受体ER-α36和EGFR高表达，并且两者存在正相关，同时发现初级胆汁酸具有类雌激素作用。初步研究显示，胆酸和鹅脱氧胆酸可上调肝癌细胞中ER-α36和EGFR的表达，升高ERK的磷酸化水平，促进细胞生长；而沉默ER-α36的肝癌重组细胞中，则无此现象。提示胆酸和鹅脱氧胆酸可能通过ER-α36介导的信号通路，利用ER-α36-EGFR调节环路，促进肝癌细胞生长。据此,申请者提出了初级胆汁酸具有类雌激素的作用，可促进肝癌细胞生长的全新理论，并拟从人体、动物、肝癌（干）细胞、蛋白及基因水平上获得初级胆汁酸-ER-α36信号通路，ER-α36-EGFR调节环路的作用，促进肝癌细胞生长的机制等大量重要数据,具有重大的临床及生物学意义。