Epigenetic Regulation Of Sex-dependent Liver Cancer

性别依赖性肝癌的表观遗传调控

• 批准号: 8095415
• 负责人: ARLIN B ROGERS
• 金额: $ 19.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095415
• 关键词: Acute-Phase Reaction; Address; Affect; Animals; Binding; Castration; Cell Line; Cell Nucleus; Cells; Characteristics; Chemical Injury; Chromatin; Chromosome abnormality; Chronic; Complement; DNA; DNA Sequence; Diethylnitrosamine; EP300 gene; Elderly; Epigenetic Process; Exhibits; Female; Feminine; Gender; Gene Expression; Genes; Genetic Transcription; Gonadal Steroid Hormones; Hepatocarcinogenesis; Hepatocyte; Histones; Hormonal; Hormones; Human; Hypersensitivity; Immunity; In Vitro; Incidence; Inflammation; Inflammatory Response; Interferon Type II; Interleukin-6; Interruption; Investigation; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Masculine; Mediating; Methylation; Modeling; Modification; Molecular; Mus; NF-kappa B; Nuclear Translocation; Nucleosomes; Plant Roots; Play; Post-Translational Protein Processing; Predisposition; Primary carcinoma of the liver cells; Process; Regulation; Relaxation; Reporting; Response Elements; Rodent; Role; Signal Transduction; Somatotropin; System; TNF gene; Testing; Time; Tumor Promotion; United States; Woman; base; cancer risk; chromatin remodeling; continuous cell line; cytokine; gene induction; genome-wide; hepatocyte nuclear factor; hepatoma cell; histone-binding proteins; imprint; in vivo; male; member; men; novel; programs; response; sex; sexual dimorphism; transcription factor; tumor

DESCRIPTION (provided by applicant): Hepatocellular carcinoma HCC) arises in men more than three times as often as women. Liver cancer also disproportionately affects male rodents, providing a valuable model to study mechanisms of sex-dependent hepatocarcinogenesis. We and others have shown that proinflammatory cytokines, not sex hormones, are the primary drivers of male tumor promotion. However, the process is not cytokine-specific. Interruption of either TNF-a, IFN-g or IL-6 reduces experimental liver cancer in male mice. Therefore, cancer predilection appears to be an innate characteristic of the masculinized liver. Sex-dependent hepatocyte programming, not upstream immunity, may explain gender-dimorphic tumor incidence. We have reported that HCC in male mice is associated with loss of a sex-specific genome-wide transcriptional signature, a process termed liver-gender disruption. Such pan-chromosomal alterations implicate chromatin disruption in hepatocellular transformation. Moreover, we and others have shown that male HCC susceptibility is maturationally imprinted, as there is a decreasing benefit of castration with advancing age. Liver masculinization is enacted by pulsatile growth hormone from the pituitary. Hepatocytes transduce this signal through Stat5b, which translocates to the nucleus and initiates the male transcription program. Liver masculinization involves the synchronous alteration of thousands of genes, suggesting involvement of root-level chromatin modifiers. Nevertheless, while nucleosomal relaxation may facilitate required Stat5b access to g-associated sequences (GAS) and other DNA motifs, an unintended consequence might be disproportionate binding of closely related proinflammatory transcription factors. Because of this, we hypothesize that masculine Stat5b-dependent epigenetic remodeling invokes chromatin hypersensitivity to tumor-promoting proinflammatory cytokines. Unfortunately, molecular studies of gender-specific hepatocyte function have been hampered by the lack of a suitable continuous cell line. We have developed a sexually dimorphic continuous hepatocyte culture system, and propose here to use it to probe epigenetic mechanisms that define a chromatin state as masculine or feminine. Next, we will test whether the masculine epigenetic profile increases sensitivity to proinflammatory cytokines by facilitating access of transcription factors (Stat1, Stat3, NF-kB) to cognate DNA sequences. Cell studies will be complemented with comprehensive in vivo epigenetic profiling of male and female liver in wild- type C57BL/6 and Stat5b-/- mice. A proinflammatory chemical injury model (DEN) will be used to assess transcription factor binding and acute-phase responses, with an emphasis on sexually dimorphic genes. Finally, we will determine whether Stat5b deficiency is sufficient to protect male mice from DEN-initiated HCC, suggesting a common downstream mechanism for susceptibility to inflammation-associated liver cancer. These studies are the first to define epigenetic modifiers of liver sexual differentiation, and to interrogate a novel mechanism of gender-specific tumor promotion predicated on chromatin sensitivity to inflammation. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma, the fastest rising cancer in the United States, exhibits marked gender disparity. These studies explore a cellular basis for liver sexual differentiation based on DNA and associated protein modifications, and show how inflammation may selectively increase cancer risk in men.

描述（由申请人提供）：肝细胞癌（HCC）在男性中的发病率是女性的三倍多。肝癌也不成比例地影响雄性啮齿动物，为研究性别依赖性肝癌发生机制提供了一个有价值的模型。我们和其他人已经证明，促炎细胞因子，而不是性激素，是男性肿瘤促进的主要驱动因素。然而，该过程不是细胞因子特异性的。阻断 TNF-a、IFN-g 或 IL-6 可以减少雄性小鼠的实验性肝癌。因此，癌症倾向似乎是男性化肝脏的先天特征。性别依赖性肝细胞编程，而不是上游免疫，可以解释性别二态性肿瘤的发病率。我们报道称，雄性小鼠的肝癌与性别特异性全基因组转录特征的丧失有关，这一过程被称为肝脏性别破坏。这种全染色体的改变意味着肝细胞转化中染色质的破坏。此外，我们和其他人已经表明，男性 HCC 的易感性具有成熟的印记，因为随着年龄的增长，去势的好处逐渐减少。肝脏男性化是由垂体的脉动生长激素实现的。肝细胞通过 Stat5b 转导该信号，该信号易位至细胞核并启动雄性转录程序。肝脏男性化涉及数千个基因的同步改变，表明根级染色质修饰剂的参与。然而，虽然核小体松弛可能促进所需的 Stat5b 接触 g 相关序列 (GAS) 和其他 DNA 基序，但意想不到的后果可能是密切相关的促炎转录因子的不成比例的结合。因此，我们假设男性 Stat5b 依赖性表观遗传重塑会引发染色质对促肿瘤促炎细胞因子的超敏反应。不幸的是，由于缺乏合适的连续细胞系，性别特异性肝细胞功能的分子研究受到阻碍。我们开发了一种性别二态性连续肝细胞培养系统，并在此建议用它来探索将染色质状态定义为男性或女性的表观遗传机制。接下来，我们将测试男性表观遗传特征是否通过促进转录因子（Stat1、Stat3、NF-kB）接近同源 DNA 序列来增加对促炎细胞因子的敏感性。细胞研究将通过对野生型 C57BL/6 和 Stat5b-/- 小鼠的雄性和雌性肝脏进行全面的体内表观遗传分析来补充。促炎化学损伤模型（DEN）将用于评估转录因子结合和急性期反应，重点是性二态性基因。最后，我们将确定 Stat5b 缺陷是否足以保护雄性小鼠免受 DEN 引发的 HCC 的侵害，这表明了炎症相关肝癌易感性的常见下游机制。这些研究首次定义了肝脏性别分化的表观遗传修饰因子，并探讨了基于染色质对炎症敏感性的性别特异性肿瘤促进的新机制。 公共卫生相关性：肝细胞癌是美国增长最快的癌症，表现出明显的性别差异。这些研究探索了基于 DNA 和相关蛋白质修饰的肝脏性别分化的细胞基础，并表明炎症如何选择性地增加男性癌症风险。