The Role of Long Noncoding RNAs in Cancer

肝细胞癌（HCC）是美国第五大常见恶性肿瘤，其发病率为100%。 在退伍军人中也同样高。虽然肝癌切除术已被证明是一种有效的治疗方法 对于局限性疾病，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方面的拨款建议，以研究 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， 氧气也存在脂质和氨基酸代谢的改变。然而，目前，我们所知甚少， 这种恶性代谢开关在癌症中是如何调节的。线粒体是主调节器， 调节代谢重编程恶性肿瘤细胞中的线粒体在结构和功能上与 那些在正常细胞中的细胞，其特征在于活性氧物质的过度产生。长非编码 RNA（lncRNA） 是代谢的关键调节因子，可以在表观遗传学上调节线粒体活性。这些 lncRNA可以从线粒体基因组或核基因组转录，并且lncRNA可以从线粒体基因组或核基因组转录。 从线粒体到细胞质再到细胞核。具体目标1： 人正常肝脏线粒体lncRNA， 肝细胞 癌细胞系将被广泛地分析， 以了解哪些特定的lncRNA参与了致癌作用。lncRNA的分子机制 在线粒体和细胞核之间来回穿梭将被确定。具体目标2 这些lncRNA的作用将被评估，以获得lncRNA如何使用表观遗传的机制的理解。 启动或传播的过程 肝细胞 癌症，以便制定预防或治疗癌症的策略， 疾病除了培养细胞系，我们还将创造类肿瘤，类器官， 肝细胞 癌症干细胞这些类瘤在体外重演了恶性肿瘤的发展， 提供了一个模型系统，以了解哪些lncRNA启动，传播和维持恶性状态。 这项资助的创新方面包括对lncRNA在癌症中的作用的新理解， 在发育和癌症生物学中具有广泛适用性的几种新型分子表观遗传工具中， 以及建立癌症中与肿瘤相关的lncRNA的新数据库。的最终目标 该项目是为了了解更多关于病理生理学和肿瘤发生， 肝细胞 这样新药 可以发现靶点和/或生物标志物，以帮助诊断和治疗这种致命的癌症， 男性和女性退伍军人。

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.