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）是世界上一种重要且致命的癌症。慢性肝炎病毒感染是HCC发展的最重要危险因素，特别是在亚洲，非洲和亚马逊流域的人群中。重要的是，在感染B型肝炎病毒（HBV）的HCC患者中存在显著的性别差异，根据地理位置，男女比例高达6：1。目前，这种男性占主导地位的疾病的确切病因尚不确定。最近的研究表明，HBV基因组上的病毒癌基因HBx的表达受雄激素（雄性激素）和雄激素受体（AR）的调节。HBx可以激活AR，从而为其自身的表达和致癌功能产生正反馈回路。对Y染色体上的另一种癌基因睾丸特异性蛋白Y编码（TSPY）的研究表明，TSPY作为AR反式激活的共激活剂和HBx蛋白的稳定剂，可以对HBx表达和肿瘤发生产生显着的男性显性效应。TSPY是一种参与干细胞增殖和减数分裂的雄性生殖细胞因子，但当在不相容的体细胞中异位表达时，它作为一种致癌基因发挥作用。有趣的是，存在TSPY的X同源物TSPX，其具有相反的性质并充当肿瘤抑制剂。TSPX共抑制AR反式激活并结合但促进HBx蛋白酶体降解。与TSPY分离后，TSPX仍具有调节正常细胞周期进程、促进病毒蛋白降解和抑制病毒基因表达的管家功能。TSPY破坏TSPX功能，并促进慢性HBV感染人群中的病毒肿瘤发生。TSPY可通过增强HBx基因的AR反式激活和维持HBx蛋白的稳定性来加重HBx的致癌功能。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，我们将阐明参与TSPX促进HBx降解的泛素依赖性和非依赖性途径的机制。我们将定义负责TSPY和TSPX与HBx蛋白酶体降解的相互作用和调节的结构域。我们将研究TSPX中的结构域（TSPY中不存在）可以在HBx和蛋白酶体机制之间发挥拴系和增强子功能的假设。其次，我们计划通过确认TSPX和TSPY与AR的相互作用并描绘TSPY和TSPX分别与AR共激活和共抑制HBx反式激活的关键结构域，评估AR反式激活中HBx基因启动子上游远端增强子I位置处的三个推定雄激素应答元件（战神）。我们将研究TSPY对HBx启动子活性的功能。了解TSPY如何破坏TSPX功能并加剧HBx表达和蛋白质稳定性，将对这对同源癌基因和肿瘤抑制基因在HBV相关肝癌发生中男性主导的发病机制中的潜在贡献提供重要见解。 公共卫生相关性：肝细胞癌是世界范围内常见的致命性肝癌，尤其是在慢性肝炎病毒感染人群中。值得注意的是，在感染B型肝炎病毒的肝细胞癌患者中，存在着有利于男性的关键性别差异。在疾病过程中这种男性偏好的原因尚不清楚。最近的研究已经确定了一个致癌基因（癌基因），命名为TSPY的人类Y（男性专用）染色体上，影响表达和蛋白质稳定性的肝炎B病毒癌基因，称为HBx。重要的是，在X染色体上存在TSPY的同源物，命名为TSPX，其具有与HBx相反的性质，并作为肿瘤抑制剂发挥作用。本研究旨在阐明这对同源癌基因和抑癌基因在B型肝炎病毒感染人群肝细胞癌发生中对HBx和男性优势的作用。