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

肝癌和胃肠道癌症中 TGF-β 通路成员与表观调节因子之间的细胞相互作用

• 批准号: 10405205
• 负责人: Lopa Mishra
• 金额: $ 36.49万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405205
• 关键词: Acetylation; Age; Aging; Automobile Driving; Beckwith-Wiedemann Syndrome; CCCTC-binding factor; CRISPR/Cas technology; Cancer Control; Cancer Model; Cell Line; Chromatin; Collaborations; Complement Factor B; Complex; Data; Data Analyses; Databases; Disease; Drug resistance; Epigenetic Process; Event; Family; Gastrointestinal Neoplasms; Genes; Genetic Models; Genetic Transcription; Genetically Engineered Mouse; High-Risk Cancer; Histone Deacetylase; Human; Immune; In Vitro; Inflammation; Lifting; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Molecular; Mus; Mutant Strains Mice; Nicotinamide adenine dinucleotide; Pathway interactions; Pattern; Phenocopy; Phenotype; Play; Population; Portraits; Primary carcinoma of the liver cells; Property; RNA-Directed DNA Polymerase; Regulation; Risk; Role; SIRT1 gene; Signal Transduction; Signaling Molecule; Sirtuins; Stem cell pluripotency; TGF Beta Signaling Pathway; Telomerase; The Cancer Genome Atlas; Tissues; Transforming Growth Factor beta; Treatment Failure; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Validation; aldehyde dehydrogenase 1; cBioPortal; cancer stem cell; cancer subtypes; carcinogenesis; cell behavior; cell transformation; cofactor; epigenetic regulation; gastrointestinal; human stem cells; imprint; in vivo; insight; liver inflammation; member; mouse genetics; mouse model; mutant; novel; premalignant; stem cell differentiation; stem cell genes; stem cell homeostasis; stem cells; stem-like cell; targeted treatment; tumor; tumor progression; tumorigenesis

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)

联系 PD/PI：Mishra、Lopa Project-001 (001) 抽象的 转化生长因子-β (TGF-β) 是干细胞分化、表观遗传的有效调节剂 改变、炎症、肿瘤抑制和肿瘤进展。然而，迄今为止，TGF-β的作用 肝脏和胃肠道（GI）肿瘤中处于这些特定阶段的成员仍不清楚。我们有 发现 TGF-β 信号分子 Smad3 及其接头 β2SP 在抑制干细胞中的独特作用 转变为癌症。我们观察到与人类干细胞疾病几乎相同的表型，具有高 TGF-β 信号传导中罹患癌症（包括肝癌和胃肠道癌症）、贝克威斯-维德曼综合征 (BWS) 的风险 - 我们生成的缺陷型（β2SP+/-- 和 β2SP+/-/Smad3+/-）小鼠。我们观察到多个机构的放松管制 包括干细胞基因（如 ALDH1）和增加水平的分子（如端粒酶） (TERT) 在我们的 TGF-β 信号传导缺陷的小鼠突变组织和 BWS 细胞系中，破坏了 染色质绝缘体 CTCF 驱动的 TERT 调节。我们来自 HCC TCGA 分析的初步数据表明 Sirtuin 通路和 TGF-β 成员之间存在显着的表达模式相关性。此外， SIRT6 水平在 HCC 以及缺乏 TGF-β 信号传导的小鼠突变体组织中降低； SIRT6 突变体会​​导致严重的肝脏炎症和癌症（在老年小鼠中），从而提供癌前病变 以及 HCC 的衰老癌症模型。我们的假设是肿瘤发生是通过解除 TERT 的 TGF-β/CTCF 依赖性调节缺陷导致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 SIRT6 相互作用，从而导致 随后干细胞稳态的破坏导致肝癌和胃肠道癌症。 为了探索这一假设，我们提出以下目标： 目标 1：定义机制 CTCF、β2SP 和 Smad3 三联复合物调节 TERT 和 SIRT6，以及干细胞稳态； 通过体外和体内相互作用研究 TGF-β、TERT 和 SIRT6 之间的协作， 可能为干细胞驱动的肿瘤发生中涉及的开关提供新的认识。目标 2： 开发 TGF-β 通路的全面分子肖像，包括 Sirtuin 家族和 TERT 肝癌和胃肠道癌症，通过 TCGA、cBioPortal 和 Oncomine 扩展当前对 HCC 的分析 数据库。对 TGF-β 信号通路效应器作用和我们的小鼠模型的深入了解，提供了 研究 HCC 和 GI 癌症中干细胞转化的强大方法。 项目总结/摘要第 334 页 联系 PD/PI：Mishra、Lopa Project-001 (001)