The Role of KLF6 Tumor Suppressor in Hepatocellular Cancer

阐明从慢性肝损伤和纤维化到肝细胞癌(HCC)的分子事件弧形仍然是研究肝病学中最基本的挑战。本应用的总体目标是阐明KLF6肿瘤抑制因子在肝细胞内稳态、损伤和癌症中的作用。这一目标是基于以下证据：a)锌指转录因子KLF6在丙型肝炎病毒相关的肝细胞癌中频繁发生失活。此外，KLF6显性负剪接形式KLF6SV1的过表达有助于晚期人类肝癌的致癌；b)KLF6/-小鼠表现为正常，但在单剂量致癌剂DEN后肿瘤大小和数量显著增加。在其新发现的肿瘤抑制机制中，野生型KLF6在转录上抑制Hdm2/MDM2，这是一种泛素连接酶，通常促进P53肿瘤抑制因子的蛋白酶体降解；c)肝细胞特异性缺失KLF6(‘KLF6Hep’)的小鼠发生自发性肝脏脂肪变性和高血糖。肝细胞中KLF6基因缺失后，一个明显下调的候选靶基因是葡糖激酶。基于这些数据，修改的假设是：1)KLF6通过转录调控控制肝脏脂肪和/或碳水化合物代谢的关键基因，包括葡糖激酶，维持肝脏的动态平衡；2)KLF6介导的对Hdm2/MDM2的抑制被KLF6SV1拮抗，从而增加MDM2调节的P53的降解。

Illuminating the arc of molecular events from chronic hepatic injury and fibrosis through hepatocellular carcinoma (HCC) remains the most fundamental challenge in investigative hepatology The overall goal of this application is to elucidate the role of the KLF6 tumor suppressor in hepatocellular homeostasis, injury and cancer. This goal is based on evidence that: a) Inactivation of KLF6, a zinc finger transcription factor, occurs frequently in HCV-associated HCC. Moreover, overexpression of a KLF6 dominant negative splice form, KLF6SV1, contributes to carcinognesis in advanced human HCC; b) KLF6 +/- mice appear phenotypically normal but have markedly increased tumor size and number after a single dose of the carcinogen DEN. Among its newly uncovered tumor suppressor mechanisms, wild type KLF6 transcriptionally represses the hdm2/mdm2, a ubiquitin ligase that normally promotes proteosomal degradation of the p53 tumor suppressor; c) mice with hepatocyte-specific deletion of KLF6 (‘ KLF6Hep’) develop spontaneous hepatic steatosis and hyperglycemia. One candidate target gene markedly down-regulated by deletion of KLF6 in hepatocytes is glucokinase. Based on these data the revised hypotheses are: 1) KLF6 preserves hepatic homeostasis through transcriptional regulation of key genes controlling hepatic lipid and/or carbohydrate metabolism, including glucokinase; 2) KLF6-mediated repression of hdm2/mdm2 is antagonized by KLF6SV1, thereby increasing MDM2- regulated p53 degradation.