Mechanism of DLC1-mediated tumor suppression

描述(申请人提供)：在肝癌中缺失1(DLC1)是一种局灶性黏附蛋白，包含多个结构域，包括SAM(无菌α基序)、RhoGAP(RhoGTP酶激活蛋白)和START(类固醇生成急性调节(STAR)相关的脂转移)。它最初是作为一种潜在的抑癌基因被分离出来的，在肝细胞癌中经常缺失。进一步的研究表明，通过基因组缺失或DNA甲基化导致的DLC1表达下调与多种癌症类型有关，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。在前列腺癌和结肠癌中已经发现了DLC1基因的突变，这种突变会削弱其表达和功能。大量的体外实验数据表明，DLc1‘S的许多生物学功能与其通过DLc1’S RhoGAP结构域对RhoA途径的负调控有关。另一方面，局灶性黏附定位也是DLC 1的S抑制肿瘤细胞生长所必需的。虽然RhoGAP结构域在DLC 1的S功能中的关键作用已经确定，但对DLC 1的其他结构域和新功能的研究还不够深入。此外，DLC1在细胞培养系统和动物体内介导的肿瘤抑制机制仍有待建立。我们假设DLC1是一种肿瘤抑制因子，通过其多个结构域调节包括细胞黏附、迁移和血管生成在内的细胞事件；并且它的表达或功能的丧失会增加前列腺癌的风险。这项建议的总体目标是系统地确定DLC1的结构域功能并阐明其分子机制；研究DLC1的新功能，如其在血管生成中的作用；以及展示其在小鼠前列腺中的肿瘤抑制作用，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。1.研究DLC 1调控细胞形态、黏附、迁移和致瘤性的分子机制2.发现DLC 1在预防前列腺癌发生发展中的新功能(S)3.证实DLC 1在小鼠前列腺癌发生发展中的作用并建立小鼠前列腺癌模型本研究的结果将有助于了解DLC 1的功能及其相关的分子机制，并为前列腺癌和其他与DLC 1基因缺失相关的癌症提供新的思路和治疗方法。

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.