Role of Cten in Prostate Cancer

描述(申请人提供)：前列腺癌是北美男性最常见的恶性肿瘤。然而，与前列腺细胞恶性转化相关的遗传事件在很大程度上是未知的。识别新的前列腺特异性基因可以提供新的标志物，并可能有助于开发新的治疗方法。Cten(C末端张力素样)是一种新的局灶性黏附分子，其在正常前列腺组织中的表达相对受限。我们已经报道，cten在前列腺癌中缺失或下调，是caspase3的靶标和凋亡过程中的效应因子，调节细胞迁移，招募肿瘤抑制因子DLc1(在肝癌1中缺失)与局灶性粘连，这种相互作用对DLc1的S肿瘤抑制活性至关重要。有趣的是，cten不仅定位于局部粘连，还定位于细胞核，这表明cten可能是一种转导分子，除了参与细胞表面的事件外，还可能参与核事件。人类cten基因位于染色体17q21上，该区域在前列腺癌中经常缺失。这些研究表明，cten是一种前列腺癌特异性肿瘤抑制因子，它的破坏会在前列腺癌中产生影响。然而，我们最近的研究表明，尽管cten在其他组织中不正常表达，但在大量结肠癌患者中过表达，这表明cten可能在结肠中具有致癌活性。因此，CTEN可能具有组织类型特异性的双重功能。在这个更新方案中，我们将继续研究cten在前列腺癌中的作用，并为cten在结肠癌中看似矛盾的功能提供一个分子机制。我们假设cten是一种前列腺特异性的肿瘤抑制因子，它在局部粘连和细胞核中发挥重要作用；cten表达/功能的改变扰乱了它的正常作用，增加了前列腺癌的风险。为了检验我们的假设，本文提出了三个具体目标。 目的1.确定CTEN在调节DLC1抑瘤活性中的作用 目的：建立cten核转位的机制及其在肿瘤发生中的作用。 目的3.利用体内系统研究cten在前列腺癌发生中的作用 将要研究的基因是一个非常独特的分子，是一种焦点黏附-核蛋白，它可能在焦点黏附调节DLC1肿瘤抑制因子，并在核内介导Wnt和雄激素信号之间的串扰。验证我们的假设将表明cten可能作为前列腺癌和其他癌症类型的新的治疗靶点。我们的动物实验将揭示cten的体内功能，并为研究前列腺癌的发生和药物筛选提供更好的小鼠前列腺癌模型。

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Identification of new prostate specific genes could provide new markers and could be instrumental for development of new treatment modalities. Cten (C-terminal tensin-like) is a new focal adhesion molecule, whose expression is relatively restricted at the normal prostate gland. We have reported that cten is absent or down-regulated in prostate cancers, is a target of caspase 3 and an effector during apoptosis, regulates cell migration, recruits a tumor suppressor, DLC1 (deleted in liver cancer 1), to focal adhesions and this interaction is critical for DLC1's tumor suppression activity. Interestingly, cten localizes not only to focal adhesions but also in the nucleus, suggesting that cten may be a transducer molecule, possibly involved in nuclear events in addition to events at the cell surface. Human cten gene is located on chromosome 17q21, a region often deleted in prostate cancer. These studies suggest that cten is a prostate-specific tumor suppressor whose disruption has repercussions in prostate cancer. However, our recent studies have shown that although not normally expressed in other tissues, cten is overexpressed in a large number of colon cancer patients, indicating that cten may possess an oncogenic activity in the colon. Therefore, cten may have dual functions that are tissue type specific. In this renewal proposal we will continually investigate the role of cten in the prostate and offer a molecular mechanism for the seemingly contradictory function of cten in colon cancer. We hypothesize that cten is a prostate-specific tumor suppressor that plays important roles at the focal adhesions and in the nucleus; and that alteration of cten expression/ function disrupts its normal actions and increases the risk for prostate cancer. Three specific aims are proposed to test our hypothesis. Aim 1. To determine the role of cten in regulating the tumor suppression activity of DLC1 Aim 2. To establish the mechanism of cten nuclear translocation and its role in tumorigenesis Aim 3. To demonstrate the function of cten in prostate tumorigenesis using in vivo systems The gene to be studied is a very unique molecule, a focal adhesion-nucleus protein that may regulate the DLC1 tumor suppressor at focal adhesions and mediate a crosstalk between Wnt and androgen signaling in the nucleus. Verification of our hypothesis would indicate a possible role for cten as a novel therapeutic target for prostate cancer and maybe other cancer types as well. Our animal studies will reveal cten's in vivo function and provide better mouse prostate cancer models for studying prostate tumorigenesis and drug screening.