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，表观遗传学的潜在调节剂 改变，注射，肿瘤抑制和肿瘤进展。但是，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处于这些特定阶段。我们有 发现了TGF-β信号传导分子Smad3及其适配器β2SP的独特作用，在抑制干细胞中 转化为癌症。我们观察到与较高的人类干细胞疾病几乎相同的表型 TGF-β信号传导中的癌症风险（包括肝脏和GI癌），Beckwith-Wiedemann综合征（BWS） 缺乏（β2SP+/ - 和β2Sp+/ - /smad3 +/-）小鼠。我们观察到多个的下调 包括干细胞基因（例如ALDH1）和分子水平升高（例如端粒酶）的分子 （TERT）在我们的TGF-β信号缺乏小鼠突变体和BWS细胞线中，并破坏 染色质绝缘子CTCF驱动的TERT调节。我们来自HCC TCGA分析的初步数据揭示了 Sirtuin途径与TGF-β成员之间的显着表达模式相关。此外， HCC中的SIRT6水平降低，在我们的小鼠突变体中缺乏TGF-β信号传导的组织中降低； SIRT6突变体会出现严重的肝脏注射和癌症（在老鼠中），这两者都提供了癌前 以及HCC衰老的癌症模型。我们的假设是，肿瘤发生是通过提升而发生的 染色质调节和表观遗传学改变了TGF-β/CTCF依赖性调节TERT， 通过与通常抑制肿瘤启动子基因的SIRT6相互作用，因此导致 随后破坏了驱动肝脏和GI癌的干细胞稳态。 为了探讨这一假设，我们提出以下目的：目标1：定义机制 CTCF，β2SP和SMAD3的三方复合物调节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， 有可能向参与干细胞驱动肿瘤发生的开关提供新的理解。目标2： 开发TGF-β途径的综合分子肖像，包括Sirtuin家族和TERT 肝脏和GI癌，通过TCGA，CBIOPORTAL和Comcomine扩展了HCC的当前分析 数据库。 TGF-β信号通路和我们的小鼠模型的效应子作用的见解，提供了一个 用于研究HCC和GI癌中干细胞转化转化的强大方法。 项目摘要/摘要页面334 联系PD/PI：Mishra，Lopa Project-001（001）