The Role of Long Noncoding RNAs in Cancer

长非编码 RNA 在癌症中的作用

基本信息

批准号：
10216170
负责人：
ANDREW R HOFFMAN
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216170
关键词：
Academic Medical Centers American Cancer Society Antineoplastic Agents Applications Grants Architecture Back Biological Markers Biological Models Blood Tests Bypass Cancer Biology Cancer Etiology Cancer cell line Cell Culture Techniques Cell Line Cell Nucleus Cells Cessation of life Chromatin Citric Acid Cycle Cytoplasm DNA DNA Methylation Databases Development Developmental Biology Diagnosis Disease Drug Targeting Energy Metabolism Epigenetic Process Excision Female Fresh Tissue Functional disorder Future Genes Genome Genomics Goals Grant Hepatocarcinogenesis Hepatocyte Human Immunoprecipitation In Situ In Vitro Incidence Knowledge Learning Lipids Localized Disease Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Maps Metabolic Metabolism Methodology Mitochondria Modality Molecular Monitor Normal Cell Normal tissue morphology Nuclear Occupations Operative Surgical Procedures Organ Organoids Oxygen Pathogenesis Patients Pharmaceutical Preparations Phenotype Play Primary carcinoma of the liver cells Process Provider Publishing RNA RNA Binding RNA-Binding Proteins Reactive Oxygen Species Reverse Transcription Role Specimen Structure Testing United States Unresectable Untranslated RNA Veterans Warburg Effect amino acid metabolism cancer cell cancer stem cell cancer surgery cancer type carcinogenesis chromosome conformation capture chronic liver disease differential expression effective therapy epigenetic regulation hepatocellular carcinoma cell line histone modification innovation interest knock-down male malignant state military veteran mitochondrial genome neoplastic cell new therapeutic target novel novel marker novel therapeutics overexpression prevent tool tumor tumor metabolism tumorigenesis

项目摘要

Hepatocellular cancer (HCC) is the 5th most common malignancy in the United States, and its incidence is equally high in the Veteran population. Although liver cancer resection has proven to be an effective treatment for localized disease, new therapeutic modalities are needed to treat unresectable disease. This is a 4-year grant proposal to study epigenetic aspects of hepatocellular cancer in order to study the pathophysiology of this deadly cancer and to begin to identify new therapeutic drug targets and/or define novel biomarkers for the disease. Metabolic reprogramming is a major hallmark of cancer cells. Due to the Warburg effect, tumor cells preferentially bypass the tricarboxylic acid cycle and switch to glycolytic energy metabolism despite available oxygen. Alterations in lipid and amino acid metabolism are also present. Currently, however, we know very little about how this malignant metabolic switch is regulated in cancer. Mitochondria are master regulators that modulate metabolic reprogramming. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and are characterized by overproduction of reactive oxygen species. Long noncoding RNAs (lncRNAs) are key regulators of metabolism that can modulate mitochondrial activity epigenetically. These lncRNAs may be transcribed from either the mitochondrial or the nuclear genomes, and the lncRNAs may be transported back and forth from the mitochondria to the cytoplasm to the nucleus. In Specific Aim 1, the mitochondrial lncRNAs in human normal liver and hepatocellular cancer cell lines will be extensively profiled, to learn which specific lncRNAs are involved in carcinogenesis. The molecular mechanisms whereby lncRNAs shuttle back and forth between the mitochondria and the nucleus will be determined. In Specific Aim 2, the roles of these lncRNAs will be assessed to gain a mechanistic understanding of how lncRNAs use epigenetic processes to initiate or propagate hepatocellular cancer in order to devise strategies to prevent or treat the disease. In addition to cultured cell lines, we will create tumoroids, organoids that are derived from hepatocellular cancer stem cells. These tumoroids recapitulate the development of malignant tumors in vitro, providing a model system to learn which lncRNAs initiate, propagate and maintain the malignant state. Innovative aspects of this grant include a new understanding of the role of lncRNAs in cancer, the development of several novel molecular epigenetic tools that have broad applicability in developmental and cancer biology, and the assembly of new databases of mitochondria-associated lncRNAs in cancer. The ultimate goal of the project is to learn more about the pathophysiology and oncogenesis of hepatocellular cancer so that new drug targets and/or biomarkers can be discovered to aid in the diagnosis and treatment of this deadly cancer in male and female Veterans.

肝细胞癌 (HCC) 是美国第五大常见恶性肿瘤，其发病率在退伍军人人口中同样高。尽管肝癌切除术已被证明是一种有效的治疗方法对于局部疾病，需要新的治疗方式来治疗不可切除的疾病。这是一个4年研究肝细胞癌表观遗传学方面的拨款提案，以研究其病理生理学这种致命的癌症，并开始确定新的治疗药物靶点和/或定义新的生物标志物疾病。代谢重编程是癌细胞的主要标志。由于瓦尔堡效应，肿瘤细胞优先绕过三羧酸循环并切换到糖酵解能量代谢，尽管有可用的氧。脂质和氨基酸代谢也发生改变。但目前我们所知甚少关于癌症中如何调节这种恶性代谢开关。线粒体是主要调节因子调节代谢重编程。恶性细胞中的线粒体在结构和功能上不同于这些存在于正常细胞中，其特征是活性氧过度产生。长非编码 RNA (lncRNA) 是代谢的关键调节因子，可以通过表观遗传学调节线粒体活性。这些 lncRNA可以从线粒体或核基因组转录，并且lncRNA可以是从线粒体到细胞质再到细胞核来回运输。在具体目标 1 中，人类正常肝脏中的线粒体lncRNA 肝细胞的癌细胞系将被广泛分析，了解哪些特定的 lncRNA 参与致癌作用。 lncRNA的分子机制线粒体和细胞核之间的来回穿梭将被确定。在具体目标 2 中，将评估这些 lncRNA 的作用，以获得对 lncRNA 如何利用表观遗传的机制理解启动或传播的过程肝细胞的癌症，以便制定预防或治疗癌症的策略疾病。除了培养的细胞系外，我们还将创建源自以下细胞的类肿瘤、类器官：肝细胞的癌症干细胞。这些类肿瘤在体外再现了恶性肿瘤的发展过程，提供一个模型系统来了解哪些 lncRNA 启动、传播和维持恶性状态。该资助的创新方面包括对 lncRNA 在癌症中的作用的新认识、开发几种在发育和癌症生物学中具有广泛适用性的新型分子表观遗传学工具，以及癌症中线粒体相关 lncRNA 新数据库的组装。该项目的最终目标是该项目的目的是了解更多关于病理生理学和肿瘤发生的信息肝细胞的癌症如此新药可以发现靶点和/或生物标志物来帮助诊断和治疗这种致命的癌症男性和女性退伍军人。