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

基本信息

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
项目类别：
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

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

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项目摘要

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（HCC）是一种致命的癌症人口。危险因素包括肝炎病毒感染，肥胖，衰老，酒精/药物滥用，有毒暴露和遗传/表观遗传易感性，共同促进遗传突变，细胞增殖和信号传导途径功能障碍，导致癌症。值得注意的是，男性受到HCC中女性的影响3至6倍。在HCC中，男性占主导地位一直是医疗领域的长期谜。男性性激素雄激素及其受体雄激素受体（AR）加剧了致癌过程，包括促进肝炎病毒复制，癌基因的激活和信号通路的激活以及抑制肿瘤抑制剂活动，从而在肝癌中发挥男性偏爱。因此，对抗雄激素有重大兴趣作为临床领域HCC治疗的治疗方法。重要的是，我们已经检测到组成型活性AR变体，例如AR-V7，在选定的HCC标本中。由于这些AR变体很重要它们在前列腺癌中的转移性进展中的作用，它们在HCC中的检测表明它们也可以施加肝癌的致癌功能。此外，我们在男性特异性癌基因TSPY相互作用并放大靶基因的AR和AR-V7反式激活，包括其自己的基因，分别依赖配体和独立的举止，从而潜在地影响 HCC患者的抗杀菌疗法的有效性。 TSPY是性腺母细胞瘤基因座的基因（GBY）在Y染色体上。它是一个细胞周期调节剂，功能障碍，可促进细胞增殖和肿瘤发生。 TSPY阳性HCC患者的存活率比阴性患者差，而核 AR/AR-V7的位置表示预后不良。因此，了解这种男性行为的机制 AR/AR-V7和Y-LASED TSPY基因之间的特定阳性反馈回路将在肝癌发生中为诊断，预后和临床试验的转化应用提供了科学基础抗雄激素作为HCC疗法的治疗剂。该项目着重于男性特异性正反馈回路的协同和致癌功能在3个特定目的下，AR/AR-V7和TSPY在肝癌发生中。首先，TSPY的表达模式，AR 和配对的HCC肿瘤/非肿瘤RNA样品和病理标本中的AR-V7将被分析为证实这种男性特异性的阳性反馈循环的存在，并评估它们的表达是否存在包括细胞学位置在内的模式可以用作患者的诊断和预后特征。其次，将研究Y位置TSPY的AR和AR-V7转录激活的机理 HCC细胞和小鼠肝脏使用流体动力转染策略。第三，TSPY的致癌功能， HCC中的AR和AR-V7将通过稳定的流体动力转染向整只小鼠的肝脏进行研究。他们的在正常条件和致瘤性易感性下，将评估诱导肝肿瘤发生的能力。对肝癌发生中协同作用机制的全球观点将被表征在差异基因表达，靶基因偏好和与细胞生长相关的癌基因，肿瘤抑制剂和信号通路的失调和肿瘤发生。我们将使用由此产生的动物模型评估抗雄激素药物作为治疗剂 HCC治疗。拟议的研究将提供有关男性分子机制的关键见解性激素受体AR/AR-V7和与Y染色体 - 叶染色体癌基因TSPY的协同作用肝癌发生中的男性特异性阳性反馈回路。该项目的成功将为科学提供基于AR/AR-V7和基于TSPY的诊断，预后和预后的转化应用基础 HCC临床管理方面的治疗策略；并将极大地使医疗保健提供给退伍军人患有肝癌或患有肝癌。