Cellular interactions between TGF-beta pathway members and epignetic regulators in liver and gastrointestinal cancers

联系PD/PI：Mishra，Lopa项目-001（001） 摘要 转化生长因子-β（TGF-β）是干细胞分化、表观遗传分化和增殖的有效调节因子。 改变、炎症、肿瘤抑制和肿瘤进展。然而，迄今为止，TGF-β的作用 在肝脏和胃肠道（GI）肿瘤的这些特定阶段的成员仍然很难界定。我们有 揭示了TGF-β信号分子Smad 3及其接头β2SP在抑制干细胞中的独特作用， 转化为癌症。我们观察到一种与人类干细胞疾病几乎相同的表型， 癌症风险（包括肝癌和胃肠道癌），Beckwith-Wiedemann综合征（BWS），TGF-β信号传导， 缺陷型（β2SP+/--和β2SP+/-/Smad 3 +/-）小鼠。我们观察到， 包括ALDH 1等干细胞基因在内的分子，以及端粒酶等分子水平的增加 在我们的TGF-β信号转导缺陷小鼠突变组织和BWS细胞系中， 染色质绝缘子CTCF驱动的调节TERT。我们的HCC TCGA分析的初步数据显示， Sirtuin通路和TGF-β成员之间存在显著的表达模式相关性。此外，本发明还提供了一种方法， SIRT 6水平在HCC中和来自TGF-β信号传导缺陷的小鼠突变体的组织中降低; SIRT 6突变体发展为严重的肝脏炎症和癌症（在老年小鼠中）， 和肝癌的衰老癌症模型。我们的假设是肿瘤发生是通过提升 通过缺陷性TGF-β/CTCF依赖性的TERT调节进行的染色质调节和表观遗传改变， 并通过与通常抑制肿瘤启动子基因的SIRT 6相互作用，从而导致 随后破坏干细胞体内平衡，从而导致肝癌和胃肠道癌。 为了探索这一假说，我们提出了以下目标：目标1：定义机制， CTCF、β2SP和Smad 3的三方复合物调节TERT和SIRT 6以及干细胞稳态; 通过体外和体内相互作用研究TGF-β、TERT和SIRT 6之间的协作， 潜在地提供了对干细胞驱动的肿瘤发生中涉及的开关的新理解。目标二： 开发TGF-β通路的全面分子画像，包括Sirtuin家族和TERT， 肝癌和胃肠道癌，通过TCGA，cBioPortal和Oncomine扩展了目前对HCC的分析 数据库。对TGF-β信号通路的效应作用和我们的小鼠模型的深入了解，提供了一个新的研究方向。 研究HCC和GI癌症中干细胞转化的有效方法。 项目摘要/摘要第334页 联系PD/PI：Mishra，Lopa项目-001（001）

Contact PD/PI: Mishra, Lopa Project-001 (001) ABSTRACT Transforming Growth Factor-Beta (TGF-β) is a potent regulator of stem cell differentiation, epigenetic alterations, inflammation, tumor suppression, and tumor progression. However, to date, the role of TGF-β members at these specific stages in liver and gastrointestinal (GI) tumors remains poorly delineated. We have uncovered a unique role for TGF-β signaling molecules, Smad3 and its adaptor β2SP, in suppressing stem cell transformation into cancer. We observe a nearly identical phenotype to a human stem cell disorder with a high risk of cancer (that include liver and GI cancers), Beckwith-Wiedemann syndrome (BWS), in TGF-β signaling- deficient (β2SP+/-- and β2SP+/-/Smad3+/-) mice that we have generated. We observe a de-regulation of multiple molecules including stem cell genes such as ALDH1 and increased levels of molecules such as telomerase (TERT) in our TGF-β signaling-deficient mouse mutant tissues and BWS-cell lines, with disruption of chromatin insulator CTCF-driven regulation of TERT. Our preliminary data from HCC TCGA analyses reveal a significant expression pattern correlation between the Sirtuin pathway and TGF-β members. In addition, SIRT6 levels are decreased in HCCs, and in tissues from our mouse mutants deficient in TGF-β signaling; SIRT6 mutants develop a severe liver inflammation and cancer (in older mice), providing both a precancerous and an aging cancer model for HCC. Our hypothesis is that the tumorigenesis occurs through a lifting of chromatin modulation and epigenetic alterations by defective TGF-β/CTCF-dependent regulation of TERT, and through interactions with SIRT6 that normally suppress tumor promoter genes, thus leading to subsequent disruption of stem cell homeostasis that drives liver and GI cancers. To explore this hypothesis, we propose the following aims: Aim 1: Define mechanisms by which the tripartite complex of CTCF, β2SP and Smad3 regulates TERT and SIRT6, as well as stem cell homeostasis; Investigate the collaboration between TGF-β, TERT and SIRT6 through in vitro and in vivo interactions, potentially providing new understanding into switches involved in stem cell driven tumorigenesis. Aim 2: Develop a comprehensive molecular portrait of the TGF-β pathway, including the Sirtuin family and TERT in liver and GI cancers, extending the current analysis of HCCs through TCGA, cBioPortal and Oncomine databases. The insight into the effector role of the TGF-β signaling pathway and our mouse models, provide a powerful approach for investigating the switch to stem cell transformation in HCC and GI cancers. Project Summary/Abstract Page 334 Contact PD/PI: Mishra, Lopa Project-001 (001)