Molecular Mechanisms of a Male-Specific Positive Feedback Loop in Liver Cancer

肝癌男性特异性正反馈环的分子机制

• 批准号: 10202474
• 负责人: YUN-FAI CHRIS LAU
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202474
• 关键词: Affect; Aging; Alcoholism; Alcohols; American; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Animals; Biological Process; CDC2 gene; Cancer Patient; Cell Cycle; Cell Proliferation; ChIP-seq; Chronic Hepatitis; Clinical; Clinical Management; Clinical Trials; Collaborations; Cyclin B; Cytology; DNA Sequence Alteration; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Effectiveness; Elements; Enhancers; Epigenetic Process; Etiology; Event; Feedback; Foundations; Functional disorder; Gender; Gene Expression Profile; Genes; Genetic; Goals; Gonadal Steroid Hormones; Gonadoblastoma; Health Benefit; Hepatic; Hepatocarcinogenesis; Hepatocyte; Hormone Receptor; Human; Length; Ligand Binding Domain; Ligands; Liver; Location; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Mediating; Medical; Molecular; Mus; Mutation; Neoplasm Metastasis; Nuclear; Obesity; Oncogene Activation; Oncogenes; Oncogenic; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Predisposition; Primary carcinoma of the liver cells; Procedures; Process; Prognosis; RNA; Regulation; Research; Research Personnel; Risk Factors; Role; Sampling; Sex Differences; Signal Pathway; Signal Transduction; Somatic Cell; Specimen; Survival Rate; Techniques; Testis; Therapeutic; Time; Tissue-Specific Gene Expression; Toxicant exposure; Transactivation; Transcriptional Activation; Transfection; Transgenes; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Veterans; Viral hepatitis; Virus Replication; Woman; Y Chromosome; Y protein; androgen sensitive; base; cell growth; clinical application; effectiveness outcome; genetic signature; health care delivery; health management; humanized mouse; in vivo; insight; interest; male; male sex hormones; man; men; mouse model; neoplastic cell; outcome prediction; overexpression; personalized management; pre-clinical; precision medicine; preference; prognostic signature; promoter; receptor; sexual dimorphism; sperm cell; success; therapeutically effective; transcriptome; transcriptome sequencing; treatment planning; treatment strategy; tumor; tumorigenesis; tumorigenic

Hepatocellular carcinoma (HCC) is a deadly cancer that affects more Veterans than the general American population. Risk factors include hepatitis virus infection, obesity, aging, alcohol/drug abuses, toxic exposure, and genetic/epigenetic predisposition, which collectively promote genetic mutations, cell proliferation and signaling pathway dysfunctions, leading to cancer. Significantly, men are affected 3 to 6 times higher than women in HCC. The male predominance in HCC has been a long-standing enigma in the medical field. The male sex hormone androgen and its receptor, androgen receptor (AR), exacerbate the oncogenic processes, including promotion of hepatitis viral replication, activation of oncogenes and signaling pathways, and repressing tumor suppressor activities, thereby exerting male preference in liver cancer. Hence, there are significant interests in antiandrogens as therapeutics in treatments of HCC in the clinical field. Importantly, we have detected the expression of constitutively active AR variants, e.g. AR-V7, in selected HCC specimens. Since these AR variants play important roles in metastatic advances in prostate cancer, their detection in HCC suggests that they could also exert oncogenic functions in liver cancer. Furthermore, we have identified a male-specific positive feedback loop, in which a male-specific oncogene TSPY interacts and amplifies AR and AR-V7 transactivation of target genes, including its own gene, in ligand-dependent and independent manners respectively, thereby potentially affecting the effectiveness of antiandrogen therapeutics for HCC patients. TSPY is the gene for the gonadoblastoma locus (GBY) on the Y chromosome. It is a cell cycle regulator, dysfunction of which promotes cell proliferation and oncogenesis. TSPY-positive HCC patients have worse survival rate than the negative ones while nuclear locations of AR/AR-V7 signify poor prognosis. Hence, understanding the mechanisms of actions of this male- specific positive feedback loop between AR/AR-V7 and the Y-located TSPY gene in hepatocarcinogenesis will provide the scientific foundation for translational applications in diagnosis, prognosis and clinical trials of antiandrogens as therapeutics in treatments of HCC. The project focuses on the synergistic and oncogenic functions of the male-specific positive feedback loop of AR/AR-V7 and TSPY in hepatocarcinogenesis under 3 specific aims. First, the expression patterns of TSPY, AR and AR-V7 in paired HCC tumor/non-tumor RNA samples and pathological specimens will be analyzed to substantiate the existence of such male-specific positive feedback loop and to evaluate if their expression patterns, including cytological locations, can be used as diagnostic and prognostic signatures for the patients. Second, the mechanisms of AR and AR-V7 transcriptional activation of the Y-located TSPY will be studied in HCC cells and mouse livers using hydrodynamic transfection strategy. Third, the oncogenic functions of TSPY, AR, and AR-V7 in HCC will be studied by stable hydrodynamic transfection to the livers of whole mice. Their ability to induce hepatic oncogenesis will be evaluated under normal conditions and tumorigenic predisposition. The global views on the mechanisms of their synergistic actions in hepatocarcinogenesis will be characterized with transcriptome and cistrome analyses in terms of differential gene expression, target gene preferences, and dysregulation of oncogenes, tumor suppressors and signaling pathways associated with cell growth, proliferation and tumorigenesis. We will use the resulting animal models to evaluate antiandrogen drugs as therapeutics in HCC treatments. The proposed research will provide critical insights on the molecular mechanisms of the male sex hormone receptor AR/AR-V7 and synergistic actions with the Y chromosome-located oncogene TSPY in the male-specific positive feedback loop in hepatocarcinogenesis. Success of the project will provide the scientific basis for translational applications in development of AR/AR-V7 and TSPY-based diagnosis, prognosis and therapeutic strategies in clinical management of HCC; and will greatly benefit the health care delivery to the Veterans predisposed to or suffering from liver cancer.

肝细胞癌是一种致命的癌症，比普通美国人影响更多的退伍军人 人口。危险因素包括肝炎病毒感染、肥胖、衰老、酗酒/滥用药物、接触有毒物质以及 遗传/表观遗传易感性，共同促进基因突变、细胞增殖和信号传递 途径功能障碍，导致癌症。值得注意的是，男性在肝细胞癌中的发病率是女性的3到6倍。 男性在肝细胞癌中的优势地位一直是医学界的一个谜。男性荷尔蒙 雄激素及其受体，雄激素受体(AR)，加剧了肿瘤的发生过程，包括促进 肝炎病毒复制、癌基因和信号通路的激活以及抑制肿瘤抑制因子 活动，从而在肝癌中发挥男性偏好。因此，人们对抗雄激素非常感兴趣。 作为临床领域治疗肝细胞癌的药物。重要的是，我们检测到了 成分活性AR变异体，例如AR-V7，在选定的肝细胞癌标本中。因为这些AR变种扮演着重要的角色 在前列腺癌转移进展中的作用，它们在肝细胞癌中的检测表明它们也可以发挥作用 肝癌的致癌作用。此外，我们还发现了一个男性特有的正反馈环路，在 其中男性特异性癌基因TSPY相互作用并放大靶基因的AR和AR-V7反式激活， 包括它自己的基因，分别以配体依赖和独立的方式，从而潜在地影响 抗雄激素治疗对肝癌患者的疗效。TSPY是性母细胞瘤基因 (GBY)位于Y染色体上。它是一种细胞周期调节因子，其功能障碍促进细胞增殖和 致癌作用。TSPY阳性的肝细胞癌患者的存活率低于TSPY阴性的患者 AR/AR-V7的表达部位提示预后不良。因此，了解这种雄性的行动机制-- AR/AR-V7和Y-定位TSPY基因在肝癌发生中的特异性正反馈环 为翻译在诊断、预后和临床试验中的应用提供科学依据 抗雄激素在肝细胞癌治疗中的应用 该项目的重点是男性特异性正反馈环的协同和致癌功能。 AR/AR-V7和TSPY在3种特异性靶点下在肝癌发生中的作用首先，TSPY、AR的表达模式 和AR-V7在配对的肝癌肿瘤/非肿瘤RNA样本和病理标本中进行分析，以 证实这种男性特有的正反馈环的存在，并评估它们的表达 包括细胞学位置在内的模式可作为患者的诊断和预后标志。 第二，将研究Y-定位TSPY的AR和AR-V7转录激活的机制 肝癌细胞和小鼠肝脏采用流体动力转染法。第三，TSPY的致癌功能， AR-V7和AR-V7在肝癌中的作用将通过稳定的流体动力学方法在整个小鼠的肝脏中进行研究。他们的 诱发肝脏肿瘤的能力将在正常条件下和肿瘤易感性下进行评估。 关于它们在肝癌发生中的协同作用机制的全球观点将被描述 用转录组和蛋白质组分析差异基因表达，靶基因偏好，以及 与细胞生长、增殖相关的癌基因、抑癌基因和信号通路的失调 和肿瘤的发生。我们将使用由此产生的动物模型来评估作为治疗药物的抗雄激素药物 肝细胞癌治疗。这项拟议的研究将为男性的分子机制提供重要的见解。 性激素受体AR/AR-V7及其与Y染色体癌基因TSPY的协同作用 男性特异性正反馈环在肝癌发生中的作用该项目的成功将为该项目提供科学的 在开发AR/AR-V7和基于TSPY的诊断、预后和 在肝癌的临床治疗中的策略；并将极大地有利于向 退伍军人易患肝癌或罹患肝癌。