title: Trefoil factor 1 acts to suppress senescence induced by oncogene activation during the cellular transformation process.
abstract: 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.
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Daniel R
authors: DR
authors: Radiloff
authors: Timothy P
authors: TP
authors: Wakeman
authors: Junjie
authors: J
authors: Feng
authors: Stephen
authors: S
authors: Schilling
authors: Edward
authors: E
authors: Seto
authors: Xiao-Fan
authors: XF
authors: Wang
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins