Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6591-6. doi: 10.1073/pnas.1017269108. Epub 2011 Mar 30.
Senescence is a cellular stress response characterized by persistent cell growth arrest under various stress conditions, including oncogene activation or tumor suppressor loss, which functions as a critical barrier that must be overcome to allow the progression from a precancerous or preinvasive lesion to a malignant tumor. Trefoil factor 1 (TFF1) is a secreted protein involved in maintaining the gastrointestinal epithelium by serving a tumor-suppressive role; however, TFF1 is overexpressed in several types of cancers. Here we report that TFF1 acts as a promoter of tumorigenesis in the context of prostate and pancreatic cancers by suppressing oncogene-induced senescence (OIS). Expression of TFF1 allows human prostate epithelial cells to escape OIS caused by the activated Ras oncogene or by reduced expression of the tumor suppressor PTEN, in part by the involvement of the EGF receptor-mediated pathway and inhibition of the expression of the cell cycle regulator p21. Without intrinsic promitogenic activity TFF1 may act in both autocrine and paracrine manners to enable cells to undergo the initial transformation and expansion against the restrictive microenvironment during early stage tumorigenesis. Taken together, our findings identify TFF1 as a soluble factor designed to act mainly to antagonize the OIS process to accelerate tumorigenesis.
衰老（senescence）是一种细胞应激反应，其特征是在各种应激条件下（包括癌基因激活或抑癌基因丢失）持续的细胞生长停滞。衰老作为一个关键的屏障，必须被克服，才能使肿瘤从癌前病变或侵袭前病变进展为恶性肿瘤。三叶因子 1（Trefoil factor 1，TFF1）是一种分泌蛋白，通过发挥肿瘤抑制作用来维持胃肠道上皮细胞的稳定；然而，TFF1 在多种类型的癌症中过度表达。在这里，我们报告 TFF1 通过抑制癌基因诱导的衰老（oncogene-induced senescence，OIS），在前列腺癌和胰腺癌的背景下促进肿瘤发生。TFF1 的表达使人类前列腺上皮细胞能够逃避由激活的 Ras 癌基因或肿瘤抑制因子 PTEN 表达减少引起的 OIS，部分原因是涉及表皮生长因子受体（EGF receptor，EGFR）介导的途径和细胞周期调节剂 p21 的表达抑制。没有内在的促有丝分裂活性，TFF1 可能通过自分泌和旁分泌的方式发挥作用，使细胞能够在早期肿瘤发生过程中，在限制其生长的微环境中，发生初始转化和扩增。总之，我们的研究结果表明，TFF1 是一种可溶性因子，主要设计用于拮抗 OIS 过程以加速肿瘤发生。
