Tumor Suppressor Role of ARID1A

描述（由申请人提供）：本研究的主要目的是证明ARID1A在子宫内膜相关癌发病机制中的抑瘤作用。ARID1A （BAF250A）是一种参与BRG1 SWI/SNF染色质重塑复合体形成的基因，由于我们最近在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发现了ARID1A频繁的体细胞突变，因此被认为是一种潜在的肿瘤抑制因子。在我们的研究中，绝大多数突变要么是帧外插入/删除型，导致移码突变，要么是无义突变。这两种突变模式都是经典肿瘤抑制基因的特征。与其他染色质重塑因子一样，ARID1A/BRG1复合物在调节转录活性等许多细胞功能中起着重要作用。因此，我们假设ARID1A是一种肿瘤抑制因子，其失活突变通过促进一组癌症相关基因的转录而促进子宫内膜相关癌的发展。为了验证这一假设，我们提出了三个具体目标。为了验证上述假设，我们提出以下具体目的：目的1：证明野生型ARID1A的肿瘤抑制作用。目的2：研究验证和表征候选arid1a调节基因。目的3：分析ARID1A框架内缺失突变体，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，并应对转化性癌症研究产生影响。

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.