Mechanism of DLC1-mediated tumor suppression

描述（由申请人提供）：肝癌中的β-淀粉样蛋白1（DLC 1）是一种粘着斑蛋白，含有多个结构域，包括SAM（无菌α基序）、RhoGAP（RhoGT 3激活蛋白）和START（类固醇生成急性调节（星星）相关脂质转移）。它最初是作为一个潜在的肿瘤抑制基因被分离出来的，在肝细胞癌中常被删除。进一步的研究表明，通过基因组缺失或DNA甲基化导致的DLC 1表达下调与多种癌症类型相关，包括前列腺癌、肺癌、乳腺癌、肾癌、结肠癌、子宫癌、卵巢癌和胃癌。已经在前列腺癌和结肠癌中鉴定了减弱其表达和功能的DLC 1突变。许多体外数据已经将DLC 1的许多生物学功能与其通过DLC 1的RhoGAP结构域对RhoA通路的负调节联系起来。另一方面，粘着斑定位对于DLC 1抑制肿瘤细胞生长的功能也是必不可少的。尽管RhoGAP结构域对DLC 1功能的关键作用已经确定，但DLC 1的其他结构域的作用和新功能尚未得到充分研究。此外，在细胞培养系统和动物中DLC 1介导的肿瘤抑制的潜在机制仍有待建立。我们假设DLC 1是一种肿瘤抑制因子，通过其多个结构域调节细胞事件，包括细胞粘附，迁移和血管生成;并且其表达或功能的丧失会增加前列腺癌的风险。该提案的总体目标是系统地确定DLC 1的结构域功能并阐明分子机制;研究DLC 1的新功能，例如其在血管生成中的作用;并证明其在小鼠前列腺中作为肿瘤抑制因子的作用，并开发更好的前列腺癌小鼠模型，前列腺癌是美国男性死亡的第二大原因。有具体的目标来检验我们的假设：具体目标1。DLC 1调控细胞形状、粘附、迁移和致瘤性的分子机制研究发现DLC 1在预防前列腺癌发展中的新功能DLC 1在小鼠前列腺肿瘤发生中的作用的证明和前列腺癌小鼠模型的建立拟议研究的结果将大大有助于了解DLC 1的功能及其相关分子机制，并为前列腺癌和其他癌症提供新的思路和治疗方法与DLC 1的丢失相关的癌症。 公共卫生相关性：相关性本研究旨在了解DLC 1介导的前列腺癌肿瘤抑制机制。提供DLC 1对预防前列腺肿瘤进展的贡献的证据是开发用于治疗靶向其相关途径的方法的前奏。这些知识可能适用于其他癌症，因为DLC 1的丢失与各种癌症类型有关。

DESCRIPTION (provided by applicant): Deleted in liver cancer 1 (DLC1) is a focal adhesion protein that contains multiple domains including SAM (sterile alpha motif), RhoGAP (RhoGTPase activation protein), and START (steroidogenic acute regulatory (StAR)-related lipid transfer). It was originally isolated as a potential tumor suppressor gene often deleted in hepatocellular carcinoma. Further studies have indicated that down-expression of DLC1 either by genomic deletion or DNA methylation is associated with a variety of cancer types including prostate, lung, breast, kidney, colon, uterus, ovary, and stomach. Mutations in DLC1 that attenuate its expression and function have been identified in prostate and colon cancer. Numerous in vitro data have linked many of DLC1's biological function to its negative regulation of the RhoA pathway through DLC1's RhoGAP domain. On the other hand, the focal adhesion localization is also essential for DLC1's function in suppression of tumor cell growth. Although the critical role of RhoGAP domain on DLC1's function is established, the roles of other domains and novel function of DLC1 are not well studied. In addition, the mechanisms underlying DLC1-mediated tumor suppression in cell culture systems and in an animal remain to be established. We hypothesize that DLC1 is a tumor suppressor that regulates cellular events including cell adhesion, migration, and angiogenesis through its multiple domains; and that loss of its expression or function increases the risk for prostate cancer. The overall goal of this proposal is to systematically determine the domain function of DLC1 and elucidate the molecular mechanisms; to investigate novel functions of DLC1, such as its role in angiogenesis; and to demonstrate its role as a tumor suppressor in the prostate of a mouse and develop better mouse models for prostate cancer, which is the second leading cause of death among men in the United States. There are specific aims to test our hypothesis: Specific Aim 1. Investigation of the molecular mechanism how DLC1 regulates cell shape, adhesion, migration, and tumorigenicity Specific Aim 2. Discovery of new function(s) of DLC1 in preventing prostate cancer development Specific Aim 3. Demonstration of the role of DLC1 in mouse prostate tumorigenesis and establishment of prostate cancer mouse models The results of the proposed studies will contribute significantly to knowledge of the function of DLC1 and molecular mechanisms involved, and provide new ideas and therapeutic approaches for prostate cancer and other cancers that are associated with the loss of DLC1. PUBLIC HEALTH RELEVANCE: Relevance This research is directed toward understanding the mechanism of DLC1-mediated tumor suppression in prostate cancer. Providing evidence for DLC1 contributions to prevention of prostate tumor progression is a prelude to developing methods for therapeutic targeting of its associated pathways. The knowledge may apply to other cancers, since loss of DLC1 is associated with a variety of cancer types.