The anti-senescence activity of trefoil factor 1

描述（由申请人提供）：本提案的主要目的是在小鼠模型中全面评价三叶因子1（TFF 1）在胰腺和前列腺肿瘤发生过程中的抗衰老活性，并阐明其抗衰老作用的信号传导机制。细胞衰老作为一个屏障，以防止恶性转化，但与克服衰老的机制仍然在很大程度上是未知的。因此，揭示这种机制的分子本质的新信息可能会对理解衰老作为肿瘤发生多步骤过程中的关键事件产生重大影响。作为一种分泌蛋白，TFF 1通过刺激与溃疡和炎症相关的受损组织的恢复来减少肿瘤形成，从而在胃中起到肿瘤抑制剂的作用。然而，TFF 1在来自各种器官的肿瘤组织中过度表达，例如胰腺和前列腺，在那里它通常不定位，尽管这种现象的功能意义仍然知之甚少。为了解决这个问题，我们研究了TFF 1在肿瘤发生的背景下，使用人胰腺癌和前列腺癌细胞的功能，并发现它的作用，使细胞能够突破致癌Ras诱导的衰老屏障或肿瘤抑制基因PTEN表达的减少。因此，我们的研究结果表明，在胰腺癌和前列腺癌的背景下，以前定义的肿瘤抑制因子TFF 1实际上通过使癌前病变能够克服癌基因诱导的衰老的障碍来促进肿瘤发生。为了建立在这个意想不到的发现，我们打算充分确定功能的影响，TFF 1过度表达胰腺和前列腺肿瘤的发生，采用两个完善的小鼠模型系统，其中癌基因激活诱导的衰老已被彻底记录作为致癌转化的障碍。与此同时，通过使用候选方法和基于RNAi的全基因组筛选鉴定TFF 1的受体/细胞表面结合蛋白，我们将测试TFF 1通过尚不明确的信号通路抑制细胞衰老以允许在肿瘤发生的早期阶段具有初始遗传病变的细胞的克隆扩增的假设。

DESCRIPTION (provided by applicant): The primary objective of this proposal is to fully evaluate the anti-senescence activity of Trifoil Factor 1 (TFF1) in the process of pancreatic and prostate tumorigenesis in mouse models, and elucidate the signaling mechanism underlying its anti-senescent action. Cellular senescence acts as a barrier against malignant transformation, but the mechanisms associated with the overcome of senescence remain largely unknown. Thus, new information that reveals the molecular nature of such mechanisms could have a significant impact on the understanding of senescence as a critical event in the multi-step process of tumorigenesis. As a secreted protein, TFF1 functions as a tumor suppressor in the stomach by stimulating restitution of damaged tissue associated with ulceration and inflammation to reduce tumor formation. However, TFF1 is over expressed in tumor tissues from various organs, such as pancreas and prostate, where it is not normally localized, although the functional significance of this phenomenon remains poorly understood. To address this question, we investigated the function of TFF1 in the context of tumorigenesis using human pancreatic and prostate cancer cells and found that it acts to enable cells to breach the barrier of senescence induced by oncogenic Ras or reduction in tumor suppressor PTEN expression. Thus, our results indicate that in the context of pancreatic and prostate cancer, the previously defined tumor suppressor TFF1 actually promotes tumorigenesis by enabling pre-cancerous lesions to overcome the barrier of oncogene-induced senescence. To build on this unexpected discovery, we intend to fully determine the functional impact of TFF1 over expression on pancreatic and prostate tumorigenesis by employing two well-established mouse model systems in which oncogene activation-induced senescence has been thoroughly documented to act as a barrier for oncogenic transformation. In the meantime, by the identification of receptor/cell surface binding protein of TFF1 using both a candidate-approach and a RNAi-based genome-wide screen, we will test the hypothesis that TFF1 acts to suppress cellular senescence via a still undefined signaling pathway to allow clonal expansion of cells that harbor the initial genetic lesions in the early stage of tumorigenesis.