Tumor Suppressor Role of ARID1A

描述(申请人提供)：这项研究的主要目的是证明ARID1A在子宫内膜相关癌的发病机制中的肿瘤抑制作用。ARID1A(BAF250A)是一种参与BRG1 SWI/SNF染色质重塑复合体形成的基因，最近我们发现ARID1A在46%-57%的卵巢透明细胞癌、40%的子宫内膜样癌和30%的卵巢子宫内膜样癌中频繁发生体细胞突变，因此已成为一种潜在的肿瘤抑制基因。在我们的研究中，绝大多数突变要么是导致移码的框外插入/缺失类型，要么是无义突变。这两种突变模式都是经典抑癌基因的特征。与其他染色质重塑因子一样，ARID1A/BRG1复合体在调节转录活性和许多其他细胞功能中发挥着重要作用。因此，我们假设ARID1A是一种肿瘤抑制基因，其失活突变通过促进一系列癌症相关基因的转录而促进子宫内膜相关癌的发展。为了检验这一假设，我们提出了三个具体目标。为了验证上述假设，我们提出了以下具体目标：目的1：验证野生型ARID1A的肿瘤抑制作用。目的2：研究、验证和鉴定受ARID1A调控的候选基因。目的：分析ARID1A框内缺失突变体，揭示调节ARID1a稳态蛋白水平的新机制。这项研究的结果将解决围绕ARID1A在癌症生物学中的作用的几个关键问题，并应该对转译癌症研究有意义。 公共卫生相关性：这项研究的目的是验证我们的假设，即ARID1A是一种肿瘤抑制基因，其失活突变通过促进一系列癌症相关基因的转录而促进子宫内膜相关癌的发展。这些预期的结果将为未来的研究奠定基础，这些研究旨在阐明ARID1A和SWI/SNF复合体在子宫内膜相关肿瘤发生中的生物学作用，并有助于了解染色质重塑的异常如何参与人类癌症的发展。

DESCRIPTION (provided by applicant): The main objective of this study is to demonstrate the tumor suppressor role of ARID1A in the pathogenesis of endometrium-related cancer. ARID1A (BAF250A), a gene participating in the formation of a BRG1 SWI/SNF chromatin remodeling complex, has emerged as a potential tumor suppressor because we have recently demonstrated frequent somatic mutations of ARID1A in 46%-57% of ovarian clear cell carcinomas, 40% of uterine endometrioid carcinomas and 30% of ovarian endometrioid carcinomas. In our studies, the vast majority of the mutations are either the out-of-frame insertion/deletion type causing frameshift or nonsense mutations. Both mutation patterns are characteristic of classical tumor suppressor genes. Like other chromatin remodeling factors, ARID1A/BRG1 complex plays an important role in regulating transcriptional activity among many other cellular functions. Thus, we hypothesize that ARID1A is a tumor suppressor of which inactivating mutations contribute to the development of endometrium-related carcinoma by facilitating transcription of a set of cancer- related genes. To test this hypothesis, we propose three specific aims. To test the above hypotheses, we propose the following specific aims: Aim 1: Demonstrate the tumor suppressive effects of wild-type ARID1A. Aim 2: Investigate Validate and characterize candidate ARID1A-regulated genes. Aim 3: Analyze ARID1A in- frame deletion mutants to reveal a novel mechanism in regulating the steady-state protein levels of ARID1A. The results from this study will address several critical questions centering the roles of ARID1A in cancer biology and should have implication for translational cancer research. PUBLIC HEALTH RELEVANCE: The purpose of this study is to test our hypothesis that ARID1A is a tumor suppressor of which inactivating mutations contribute to the development of endometrium-related carcinoma by facilitating transcription of a set of cancer-related genes. The expected results should be fundamental for future studies that aim at elucidating the biological roles of ARID1A and SWI/SNF complexes in endometrium-related tumorigenesis and help to understand how aberrations of chromatin remodeling participate in the development of human cancer.