The Long Noncoding RNA MALAT1 in Liver Cancer

项目描述 肝细胞癌（HCC）是第五常见的人类癌症， 癌症相关死亡的第三大原因。肿瘤通常发生在 背景慢性肝病伴炎症、组织损伤和失调 肝细胞再生最近的全基因组测序分析已经确定 MALAT 1作为人HCC中频繁突变的长非编码RNA（lncRNA）， 尽管MALAT 1调节肝癌发生的机制仍然存在， 未知目前的应用是研究生物学功能， MALAT 1在HCC中的分子机制我们假设MALAT 1是一个关键的 长的非编码RNA，通过形成lncRNA驱动肝癌发生， 终止TGF-β/R-Smad信号传导并通过与 染色质修饰蛋白，从而调节肝癌基因表达。我们进一步 假设MALAT 1和相关信号分子的抑制可能代表了一种 有效治疗策略。将对这些假设进行评估 通过补充体外生物化学和分子分析以及体内动物试验， 模型我们提出了两个相互关联的具体目标。具体目标1旨在 阐明MALAT 1在肝癌发生中的作用及机制。实验 将进行评估的假设，MALAT 1促进肝脏 通过形成促进Smad 2/3的lncRNA-蛋白质复合物的致癌作用 去磷酸化并因此终止TGF-β/R-Smad信号传导。研究还将 以检查MALAT 1与H3 K36甲基转移酶SETD 2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MALAT 1用于HCC治疗的治疗功效。的 提出的研究将进一步确定肝细胞癌的分子机制， 并为开发新靶点提供重要意义 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.