The anti-senescence activity of trefoil factor 1

描述(申请人提供)：本提案的主要目的是全面评估三叶因子1(TFF1)在小鼠胰腺和前列腺肿瘤形成过程中的抗衰老活性，并阐明其抗衰老作用的信号机制。细胞衰老起到了阻止恶性转化的屏障作用，但与克服衰老相关的机制在很大程度上仍不清楚。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形成多步骤过程中的一个关键事件产生重大影响。作为一种分泌蛋白，TFF1在胃中发挥肿瘤抑制作用，促进与溃疡和炎症相关的受损组织的修复，以减少肿瘤的形成。然而，TFF1在胰腺和前列腺等各种器官的肿瘤组织中过度表达，而这些组织通常不是定位的，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，我们使用人胰腺和前列腺癌细胞研究了TFF1在肿瘤发生过程中的功能，发现它能够使细胞突破由致癌RAS或肿瘤抑制基因PTEN表达减少所诱导的衰老屏障。因此，我们的结果表明，在胰腺癌和前列腺癌的背景下，先前定义的肿瘤抑制基因TFF1实际上通过使癌前病变克服癌基因诱导的衰老的障碍来促进肿瘤的发生。为了建立这一意想不到的发现，我们打算通过使用两个成熟的小鼠模型系统来全面确定TFF1过表达对胰腺和前列腺肿瘤发生的功能影响，在这两个模型系统中，癌基因激活诱导的衰老已被充分证明是致癌转化的屏障。同时，通过使用候选方法和基于RNAi的全基因组筛选来鉴定TFF1的受体/细胞表面结合蛋白，我们将检验TFF1通过一条仍未确定的信号途径抑制细胞衰老的假设，以允许在肿瘤发生的早期阶段包含初始遗传损伤的细胞的克隆性扩张。

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.