Sex Chromosomes and Gender Disparity in HBV-Related Hepatocellular Carcinoma

HBV 相关肝细胞癌中的性染色体和性别差异

• 批准号: 7977982
• 负责人: YUN-FAI CHRIS LAU
• 金额: $ 22.56万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-23 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977982
• 关键词: Address; Affect; Africa; Age; Alcoholism; Androgen Receptor; Androgen Response Element; Androgens; Apoptotic; Asia; Binding; Biological Assay; Cell Culture System; Cell Cycle Progression; Cell Proliferation; Chromosomes; Chronic Hepatitis; Chronic Hepatitis B; DNA; Degradation Pathway; Development; Disease; Distal; Dominant-Negative Mutation; Enhancers; Epigenetic Process; Etiology; Event; Feedback; Female; Gender; Gene Expression; Gene Structure; Genes; Genome; Genomic Instability; Geographic Locations; Germ Cells; Hepatic; Hepatitis; Hepatitis B; Hepatitis B Virus; Hepatitis Viruses; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Homologous Gene; Hormones; Hot Spot; Housekeeping; Human; Laboratories; Ligands; Liver Cirrhosis; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Meiosis; N-terminal; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Positioning Attribute; Preventive; Primary carcinoma of the liver cells; Process; Property; Proteins; Proto-Oncogenes; Regulation; Reporter; Repression; Research; Risk Factors; Role; Sex Chromosomes; Somatic Cell; Stem cells; Stretching; Suppressor Genes; Testing; Therapeutic; Transactivation; Transcriptional Regulation; Transfection; Tumor Suppressor Genes; Tumor Suppressor Proteins; Ubiquitin; Viral; Viral Cancer; Viral Genes; Viral Oncogene; Viral Proteins; Virus Diseases; Virus Replication; X Chromosome; Y Chromosome; design; human TSPY protein; in vitro Assay; insight; interest; male; men; preference; prolylarginine; promoter; protein degradation; protein expression; protein structure; public health relevance; receptor function; sex; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a significant and deadly cancer in the world. Chronic hepatitis virus infection is the most significant risk factor for HCC development, especially among populations in Asia, Africa and the Amazon Basin. Importantly, there is a significant sex disparity among the HCC patients infected with hepatitis B virus (HBV) with male to female ratio as high as 6:1, depending on geographical locations. Currently, the exact etiology of such male dominance in the disease is uncertain. Recent studies suggest that the expression of the viral oncogene, HBx, on HBV genome is regulated by androgen, the male hormone, and androgen receptor (AR). HBx, in term, can activate AR, thereby generating a positive feedback loop for its own expression and oncogenic functions. Studies of another oncogene on the Y chromosome, testis-specific protein Y encoded (TSPY), suggest that TSPY serves as a co-activator for AR transactivation and stabilizer for HBx protein and could exert significant male dominant effects on HBx expression and oncogenesis. TSPY has specialized as a male germ cell factor involved in stem cell proliferation and meiotic division, but functions as an oncogene when ectopically expressed in incompatible somatic cells. Interesting, there is a X-homologue of TSPY, TSPX, which possesses contrasting properties and acts as a tumor suppressor. TSPX co-represses AR transactivation and binds but promotes HBx proteasomal degradation. After it diverged with TSPY, TSPX maintains the housekeeping functions in modulating proper cell cycle progression, promoting viral protein degradation and repressing viral gene expression. TSPY disrupts TSPX functions, and promotes viral oncogenesis in populations chronically infected with HBV. TSPY could exacerbate HBx oncogenic functions by exaggerating the AR transactivation of HBx gene and maintaining HBx protein stability. In this exploratory project, we plan to address the roles of TSPY and TSPX in HBx protein stability and modulation AR transactivation. First, we will elucidate the mechanisms involved in TSPX promotion of HBx degradation in the ubiquitin dependent and independent pathways. We will define the domains responsible for TSPY and TSPX interactions with and modulation of HBx proteasomal degradation. We will examine the postulation that the domains in TSPX, which are absent in TSPY, could serve tethering and enhancer functions between HBx and the proteasomal machinery. Second, we plan to evaluate three putative androgen response elements (AREs) at the distal Enhancer I position upstream of the HBx gene promoter in the AR transactivation by confirming TSPX and TSPY interactions with AR and delineating the critical domains important for TSPY and TSPX co- activation and co-repression respectively with AR on HBx transactivation. We will examine TSPY functions on HBx promoter activities. Understanding how TSPY disrupts TSPX functions and exacerbates HBx expression and protein stability will shed critical insights on the potential contributions of this pair of homologous oncogene and tumor suppressor gene in the pathogenesis of male dominance in HBV-related hepatocarcinogenesis. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma is a prevalent and deadly liver cancer in the world, particularly among populations chronically infected with hepatitis viruses. Significantly, there is a critical gender disparity favoring men among hepatocellular carcinoma patients infected with hepatitis B virus. The reason for such male preference in the disease process is unknown. Recent studies have identified an oncogene (cancer gene), designated as TSPY on the human Y (male-only) chromosome that affects the expression and protein stability of the hepatitis B viral cancer gene, called HBx. Importantly, there is a homologue of TSPY, designated as TSPX, on the X chromosome, which possesses contrasting properties on HBx, and functions as a tumor suppressor. The proposed research is designed to elucidate the functions of this pair of homologous oncogene and tumor suppressor gene on HBx and male dominance in hepatocellular carcinoma development in hepatitis B virus infected populations.

描述（由申请人提供）：肝细胞癌（HCC）是世界上重要的致命癌症。慢性肝炎病毒感染是HCC发展的最重要危险因素，尤其是在亚洲，非洲和亚马逊盆地的人群中。重要的是，根据地理位置的不同，患有乙型肝炎病毒（HBV）的HCC患者的性别差异很大，男性与女性比率高6：1。当前，这种男性在疾病中的确切病因尚不确定。最近的研究表明，HBV基因组上病毒癌基因HBX的表达受雄激素，雄性激素和雄激素受体（AR）的调节。在术语上，HBX可以激活AR，从而为其自身表达和致癌功能产生正反馈回路。对Y染色体，睾丸特异性蛋白Y编码（TSPY）的另一种癌基因的研究表明，TSPY是HBX蛋白的AR反式激活和稳定剂的共激活剂，并且可能对HBX表达和发作发生产生明显的男性主导作用。 TSPY专门作为参与干细胞增殖和减数分裂分裂的雄性生殖细胞因子，但是当异位在不兼容的体细胞中表达时起到了癌基的作用。有趣的是，有一个TSPY，TSPX的X-总体学，具有对比的特性并充当肿瘤抑制器。 TSPX共抑制AR反式激活并结合，但促进了HBX蛋白酶体降解。在与TSPY差异后，TSPX在调节适当的细胞周期进程，促进病毒蛋白降解和抑制病毒基因表达方面保持管家功能。 TSPY破坏了TSPX的功能，并促进了慢性感染HBV的人群中的病毒肿瘤发生。 TSPY可能会通过夸大HBX基因的AR反式激活并维持HBX蛋白稳定性来加剧HBX HBX致癌功能。在这个探索性项目中，我们计划解决TSPY和TSPX在HBX蛋白稳定性和调节AR反式激活中的作用。首先，我们将阐明与泛素依赖性和独立途径中HBX降解有关的TSPX促进的机制。我们将定义负责与HBX蛋白酶体降解的TSPY和TSPX相互作用的域。我们将研究以下假设：TSPX中不存在的TSPX中的域可以在HBX和蛋白酶体机械之间发挥束缚和增强子功能。其次，我们计划通过确认TSPS和TSPY相互作用与AR的远端增强子I位置在HBX基因启动子上游的远端增强子I位置上的三个假定的雄激素反应元件（ARE），并与AR划定对TSPSY和TSPX共同的关键域重要在HBX反式激活上分别与AR一起激活和抑制。我们将检查HBX启动子活动的TSPY功能。了解TSPY如何破坏TSPX的功能并加剧HBX表达和蛋白质稳定性将对这对同源性癌基因和肿瘤抑制基因在与HBV相关的肝癌中的男性优势发病机理中的潜在贡献进行关键见解。 公共卫生相关性：肝细胞癌是世界上普遍且致命的肝癌，尤其是在长期感染肝炎病毒的人群中。值得注意的是，在感染丙型肝炎病毒的肝细胞癌患者中，有偏爱男性的性别差异很大。这种男性偏爱在疾病过程中的原因尚不清楚。最近的研究已经确定了一种在人Y（仅男性）染色体上指定为TSPY的致癌基因（癌症基因），该染色体影响了丙型肝炎病毒癌基因的表达和蛋白质稳定性，称为HBX。重要的是，在X染色体上有一个TSPY的同源物，被指定为TSPX，其在HBX上具有对比特性，并且作为肿瘤抑制剂的作用。拟议的研究旨在阐明这对同源性癌基因和肿瘤抑制基因在HBX上的功能，以及在肝炎病毒感染种群中肝细胞癌发育中男性优势。