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（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、非洲和亚马逊盆地的人群中。重要的是，乙肝病毒（HBV）感染的HCC患者存在显著的性别差异，男女比例高达6:1，这取决于地理位置。目前，这种男性优势的确切病因尚不清楚。最近的研究表明，HBV基因组上的病毒致癌基因HBx的表达受雄激素（雄激素）和雄激素受体（AR）的调控。就HBx而言，它可以激活AR，从而为其自身表达和致癌功能产生一个正反馈循环。对Y染色体上另一个癌基因睾丸特异性蛋白Y编码（睾丸特异性蛋白Y编码，TSPY）的研究表明，TSPY作为AR反激活的共激活因子和HBx蛋白的稳定剂，可能在HBx表达和肿瘤发生中发挥显著的男性显性作用。TSPY作为男性生殖细胞因子参与干细胞增殖和减数分裂，但当在不相容的体细胞中异位表达时，它作为致癌基因发挥作用。有趣的是，TSPY有一个x同源物，TSPX，它具有不同的特性，并作为肿瘤抑制因子。TSPX共同抑制AR交易激活和结合，但促进HBx蛋白酶体降解。在与TSPY分化后，TSPX维持了调控细胞周期进程、促进病毒蛋白降解和抑制病毒基因表达的管家功能。在慢性HBV感染人群中，TSPY破坏TSPX功能，促进病毒肿瘤发生。TSPY可能通过增强HBx基因的AR转激活，维持HBx蛋白的稳定性，从而加重HBx的致癌功能。在这个探索性项目中，我们计划研究TSPY和TSPX在HBx蛋白稳定性和调节AR转激活中的作用。首先，我们将阐明TSPX在泛素依赖和独立途径中促进HBx降解的机制。我们将定义负责TSPY和TSPX与HBx蛋白酶体降解相互作用和调节的结构域。我们将检验TSPX中不存在的结构域可能在HBx和蛋白酶体机制之间起系固和增强作用的假设。其次，我们计划通过确认TSPX和TSPY与AR的相互作用，并描述TSPY和TSPX在HBx转激活中分别与AR共激活和共抑制的关键结构域，来评估HBx基因启动子上游远端增强子I位置的三个假定的雄激素反应元件（AREs）。我们将研究TSPY对HBx启动子活性的作用。了解TSPY如何破坏TSPX功能并加剧HBx表达和蛋白稳定性，将有助于了解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优势发病机制中的潜在作用。