The Long Noncoding RNA MALAT1 in Liver Cancer

肝癌中的长非编码 RNA MALAT1

基本信息

批准号：
10304936
负责人：
Tong Wu
金额：
$ 34.07万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304936
关键词：
Animal Model Antisense Oligonucleotides BAY 54-9085 Biochemical Biological Process Cancer Etiology Cessation of life Chromatin Development Diagnosis FDA approved Gene Mutation Genes Genetic Transcription Goals Growth Hepatocarcinogenesis Hepatocyte Histone Deacetylase Histone H3 Human In Vitro Incidence Inflammation Knowledge Liver Cirrhosis Liver diseases Lysine MALAT1 gene Malignant Neoplasms Malignant neoplasm of liver Methyltransferase Modification Molecular Molecular Analysis Mutate Mutation Natural regeneration Nexavar Pathogenesis Patients Pharmaceutical Preparations Phosphorylation Pre-Clinical Model Primary carcinoma of the liver cells Prognosis Protein phosphatase Proteins SET Domain Signal Transduction Signaling Molecule Transforming Growth Factor beta Transforming Growth Factors Treatment Efficacy United States Untranslated RNA cancer cell cancer gene expression chemotherapy chronic liver disease design efficacy evaluation epigenetic regulation expectation experimental study genome sequencing histone acetyltransferase histone methyltransferase improved in vivo inhibitor new therapeutic target next generation novel novel therapeutics phosphorothioate prevent protein complex public health relevance receptor targeted treatment therapeutically effective tissue injury treatment strategy tumor tumor progression tumorigenesis whole genome

项目摘要

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.

项目描述肝细胞癌（HCC）是第五大最常见的人类癌症，也是与癌症相关死亡的第三大原因。肿瘤通常在感染，组织损伤和不调节的慢性肝病的背景肝细胞再生。最近的全基因组测序分析已经确定 Malat1作为人类HCC中经常突变的长不编码RNA（lncRNA），尽管MALAT1调节肝癌的机制仍然存在未知。提出了当前的应用来研究生物学功能， MALAT1的分子机制在HCC中。我们假设Malat1是关键长的非编码RNA通过形成lncRNA-驱动肝癌发生的RNA 终止TGF-β/R-SMAD信号转导并通过与染色质修饰蛋白因此调节肝癌基因表达。我们进一步假设抑制MALAT1和相关信号分子可能代表 HCC治疗的有效治疗策略。这些假设将被评估通过完工的体外生化和分子分析以及体内动物型号。我们提出了两个相互关联的特定目标。特定目标1旨在描述MALAT1在肝癌发生中的作用和机制。实验将进行以评估MALAT1促进肝脏的假设通过形成促进Smad2/3的lncRNA-蛋白质复合物的癌变去磷酸化，从而终止TGF-β/R-SMAD信号传导。研究也将进行检查以检查MALAT1与H3K36甲基转移酶SetD2的相互作用和其他染色质修饰蛋白。在特定目标2中，我们将评估临床前模型中抑制MALAT1对HCC治疗的治疗效率。拟议的研究将进一步定义肝的分子机制致癌作用并为新目标的发展提供了重要意义疗法。