The anti-senescence activity of trefoil factor 1

描述（由申请人提供）：本申请的主要目的是在小鼠模型中全面评估三叶油因子1 （TFF1）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机制。细胞衰老可作为恶性转化的屏障，但与克服衰老相关的机制仍在很大程度上是未知的。因此，揭示这些机制的分子性质的新信息可能对理解衰老作为肿瘤发生多步骤过程中的关键事件具有重大影响。作为一种分泌蛋白，TFF1在胃中发挥抑瘤作用，刺激与溃疡和炎症相关的受损组织恢复，减少肿瘤形成。然而，TFF1在各种器官的肿瘤组织中过表达，如胰腺和前列腺，尽管这种现象的功能意义尚不清楚，但它通常并不局限于这些器官。为了解决这个问题，我们利用人胰腺癌和前列腺癌细胞研究了TFF1在肿瘤发生过程中的功能，发现它可以使细胞突破由致癌Ras或肿瘤抑制因子PTEN表达减少诱导的衰老屏障。因此，我们的研究结果表明，在胰腺癌和前列腺癌的背景下，先前定义的肿瘤抑制因子TFF1实际上通过使癌前病变克服癌基因诱导的衰老屏障来促进肿瘤发生。在这一意外发现的基础上，我们打算通过采用两种成熟的小鼠模型系统，充分确定TFF1过表达对胰腺和前列腺肿瘤发生的功能影响，在这两种模型系统中，癌基因激活诱导的衰老已被充分记录为癌性转化的屏障。同时，通过使用候选方法和基于rnai的全基因组筛选鉴定TFF1的受体/细胞表面结合蛋白，我们将验证TFF1通过一个尚未确定的信号通路抑制细胞衰老的假设，从而允许在肿瘤发生早期具有初始遗传病变的细胞克隆扩增。

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.