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

联系PD/PI：米什拉，洛帕项目-001(001) 摘要 转化生长因子-β(β)是一种强大的干细胞分化、表观遗传学调节因子 改变、炎症、肿瘤抑制和肿瘤进展。然而，迄今为止，转化生长因子-β的作用 处于这些特定阶段的成员在肝脏和胃肠道(GI)肿瘤中的描述仍然很模糊。我们有 发现转化生长因子-β信号分子Smad3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，具有高度的 癌症风险(包括肝癌和胃肠癌)，贝克韦德曼综合征，转化生长因子-β信号转导- 我们产生的缺陷小鼠(β2SP/-和β2SP/-/Smad3/-)。我们观察到了对多个 包括ALDH1等干细胞基因在内的分子和端粒酶等分子水平升高 (TERT)在我们的转化生长因子-β信号缺陷突变小鼠组织和bws-细胞系中，并破坏 染色质绝缘子CTCF驱动的TERT调节。我们来自肝细胞癌TCGA分析的初步数据显示 Sirtuin通路和转化生长因子-β成员之间的显著表达模式相关。此外, SIRT6在肝细胞癌和我们的小鼠缺乏转化生长因子-β信号的突变体组织中的水平降低； SIRT6突变会发展成严重的肝脏炎症和癌症(在老年小鼠中)，提供了一种癌前病变 以及一种用于肝癌的衰老癌症模型。我们的假设是，肿瘤的发生是通过解除 TERT依赖于转化生长因子-β/ctcf缺陷调控的染色质调节和表观遗传学改变， 通过与SIRT6的相互作用，SIRT6通常会抑制肿瘤促进基因，从而导致 随后导致干细胞动态平衡的破坏，从而导致肝癌和胃肠道癌症。 为了探索这一假设，我们提出了以下目标：目标1：定义 β-2SP-Smad3三方复合体调控TERT和SIRT6，以及干细胞内环境的稳定； 研究转化生长因子β、端粒酶逆转录酶和SIRT6在体内外相互作用中的协同作用。 潜在地为参与干细胞驱动的肿瘤发生的开关提供了新的理解。目标2： 开发转化生长因子-β途径的全面分子图谱，包括Sirtuin家族和TERT在 肝癌和胃肠癌，通过TCGA、cBioPortalTM和Oncomine扩展目前对肝癌的分析 数据库。对转化生长因子-β信号通路和我们的小鼠模型的影响作用的洞察，提供了一种 研究肝细胞癌和胃肠道肿瘤向干细胞转化的有效方法。 项目摘要/摘要页334 联系PD/PI：米什拉，洛帕项目-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)