Mechanism of DLC1-mediated tumor suppression

描述（由申请人提供）：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 （RhoGTPase激活蛋白）和START（甾体性急性调节（StAR）相关脂质转移）。它最初是作为一种潜在的肿瘤抑制基因被分离出来的，通常在肝细胞癌中被删除。进一步的研究表明，通过基因组缺失或DNA甲基化降低dcl1的表达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发现了DLC1的突变，该突变会减弱其表达和功能。许多体外数据表明，dcl1的许多生物学功能与其通过dcl1的RhoGAP结构域对RhoA通路的负调控有关。另一方面，局灶黏附定位也是DLC1抑制肿瘤细胞生长的必要条件。虽然RhoGAP结构域在DLC1功能中的关键作用已经确立，但其他结构域的作用和DLC1的新功能尚未得到很好的研究。此外，在细胞培养系统和动物实验中，dlc1介导的肿瘤抑制机制仍有待建立。我们假设dcl1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；这种基因表达或功能的丧失会增加患前列腺癌的风险。本课题的总体目标是系统地确定dcl1的结构域功能并阐明其分子机制；研究dcl1的新功能，如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。有几个特定的目标可以检验我们的假设：dcl1调控细胞形态、粘附、迁移和致瘤性的分子机制研究发现dcl1在预防前列腺癌发展中的新功能dcl1在小鼠前列腺肿瘤发生中的作用及前列腺癌小鼠模型的建立。本研究的结果将有助于了解dcl1的功能及其分子机制，为前列腺癌及其他与dcl1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. 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.