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）的分子事件的弧仍然是研究性肝病学中最基本的挑战。本申请的总体目标是阐明KLF 6肿瘤抑制因子在肝细胞稳态、损伤和癌症中的作用。这一目标是基于以下证据：a）KLF 6（一种锌指转录因子）的失活经常发生在HCV相关的HCC中。此外，KLF 6显性负剪接形式KLF 6SV 1的过表达有助于晚期人HCC的致癌; B）KLF 6 +/-小鼠表现为表型正常，但在单剂量致癌物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KLF 6转录抑制hdm 2/mdm 2，这是一种通常促进p53肿瘤抑制因子的蛋白体降解的泛素连接酶; c）具有肝细胞特异性KLF 6缺失（“KLF 6 Hep '）的小鼠发生自发性肝脂肪变性和高血糖症。肝细胞中KLF 6缺失显著下调的一个候选靶基因是葡萄糖激酶。基于这些数据，修正的假设是：1）KLF 6通过转录调节控制肝脏脂质和/或碳水化合物代谢的关键基因（包括葡萄糖激酶）来保持肝脏稳态; 2）KLF 6介导的hdm 2/mdm 2抑制被KLF 6SV 1拮抗，从而增加MDM 2调节的p53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.