The Long Noncoding RNA MALAT1 in Liver Cancer

项目说明 肝细胞癌(肝细胞癌)是人类第五大常见癌症， 癌症相关死亡的第三大原因。肿瘤通常发生在 慢性肝病合并炎症、组织损伤和失调的背景 肝细胞再生。最近的全基因组测序分析已经确定 MALAT1作为人肝细胞癌中频繁突变的长非编码RNA(LncRNA)， 尽管MALAT1调节肝癌发生的机制仍然存在 未知。目前的应用是为了研究生物功能和 MALAT1在肝癌中的分子机制我们假设MALAT1是一个枢纽 长的非编码RNA，通过形成lncRNA-1来驱动肝癌的发生 终止转化生长因子-β/R-Smad信号转导的蛋白质复合体 染色质修饰蛋白从而调节肝癌基因的表达。我们进一步 假设MALAT1和相关信号分子的抑制可能代表一种 肝癌治疗的有效治疗策略。将对这些假设进行评估 通过体外生化和分子分析与体内动物互补 模特们。我们提出了两个相互关联的具体目标。特定目标1旨在 阐明MALAT1在肝癌发生中的作用及机制。实验 将对MALAT1促进肝脏的假设进行评估 通过形成促进Smad2/3的lncRNA-蛋白质复合体而致癌 去磷酸化，从而终止转化生长因子-β/R-Smad信号。研究还将 检测MALAT1与H3K36甲基转移酶SETD2的相互作用 和其他染色质修饰蛋白。在具体目标2中，我们将评估 在临床前模型中抑制MALAT1对肝癌治疗的疗效。这个 拟议的研究将进一步定义肝脏的分子机制。 致癌机制，为新靶点的开发提供重要意义 治疗。

Project Description Hepatocellular carcinoma (HCC) is the fifth most common human cancer and the third leading cause of cancer-related death. The tumors usually develop in the background of chronic liver diseases with inflammation, tissue injury and disregulated hepatocyte regeneration. Recent whole-genome sequencing analyses have identified MALAT1 as a frequently mutated long noncoding RNA (lncRNA) in human HCC, although the mechanism by which MALAT1 regulates hepatic carcinogenesis remains unknown. The current application is proposed to investigate the biological functions and molecular mechanisms of MALAT1 in HCC. We hypothesize that MALAT1 is a pivotal long non-coding RNA that drives hepatic carcinogenesis through formation of a lncRNA- protein complex that terminates TGF-β/R-Smad signaling and through interaction with chromatin-modifying proteins thus regulating liver cancer gene expression. We further postulate that inhibition of MALAT1 and related signaling molecules may represent an effective therapeutic strategy for HCC treatment. These hypotheses will be evaluated by complementary in vitro biochemical and molecular analyses and in vivo animal models. We propose two interrelated specific aims. Specific Aim 1 is designed to delineate the effect and mechanism of MALAT1 in liver carcinogenesis. Experiments will be carried out to evaluate the hypothesis that MALAT1 promotes liver carcinogenesis through formation of a lncRNA-protein complex that facilitates Smad2/3 de-phosphorylation and thus termination of TGF-β/R-Smad signaling. Studies will also be performed to examine MALAT1 interaction with the H3K36 methyltransferase SETD2 and other chromatin-modifying proteins. In Specific Aim 2, we will assess the therapeutic efficacy of inhibiting MALAT1 for HCC treatment in preclinical models. The proposed studies will further define the molecular mechanisms of hepatic carcinogenesis and provide important implication for development of novel target therapies.