The Role of Long Noncoding RNAs in Cancer

长非编码 RNA 在癌症中的作用

• 批准号: 10477344
• 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
• 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/10477344
• 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; 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

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.

肝细胞癌是美国第五大常见恶性肿瘤，其发病率为 在退伍军人中的比例也同样高。尽管肝癌切除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能切除的疾病。这是一个为期4年的 建议研究肝细胞癌的表观遗传学方面，以研究肝细胞癌的病理生理学 并开始寻找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一个主要标志。 由于华宝效应，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 氧气。脂类和氨基酸代谢也有改变。然而，目前我们所知甚少。 关于这种恶性代谢开关是如何在癌症中被调节的。线粒体是主要的调节器， 调节新陈代谢重新编程。恶性细胞中的线粒体在结构和功能上与 在正常细胞中，以产生过多的活性氧为特征。长非编码 RNA(LncRNAs) 是代谢的关键调节者，可以从表观遗传学上调节线粒体的活动。这些 LncRNAs可以从线粒体或核基因组转录而来，而lncRNAs可能是 从线粒体到细胞质再到细胞核的来回运输。在具体目标1中， 人正常肝和肝组织中线粒体IncRNA的表达 肝细胞 癌细胞株将被广泛分析， 了解哪些特定的lncRNAs参与了癌症的发生。LncRNAs的分子机制 线粒体和细胞核之间的往返穿梭将被确定。在具体目标2中， 将评估这些lncRNAs的作用，以获得对lncRNAs如何利用表观遗传学的机械理解 启动或传播的流程 肝细胞 为了制定预防或治疗癌症的策略 疾病。除了培养的细胞系外，我们还将创造类肿瘤，源于 肝细胞 癌症干细胞。这些类肿瘤在体外概括了恶性肿瘤的发展过程， 为了解哪些LncRNA启动、繁殖和维持恶性状态提供了一个模型系统。 这项资助的创新方面包括对lncRNAs在癌症中的作用的新的理解，开发 在发育和癌症生物学中具有广泛适用性的几种新的分子表观遗传学工具中， 以及组装癌症中与线粒体相关的lncRNA的新数据库。的最终目标是 项目是学习更多关于食道癌的病理生理学和致癌机制。 肝细胞 癌症，所以新药 靶点和/或生物标记物可以被发现来帮助诊断和治疗这种致命的癌症 男性和女性退伍军人。