Tif1 gamma Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway

作者：Vincent David F; Gout Johann; Chuvin Nicolas; Arfi Vanessa; Pommier Roxane M; Bertolino Philippe; Jonckheere Nicolas; Ripoche Doriane; Kaniewski Bastien; Martel Sylvie; Langlois Jean Baptiste; Goddard Leon Sophie; Colombe Amelie; Janier Marc; Van Seuningen Isabelle; Losson Regine; Valcourt Ulrich; Treilleux Isabelle; Dubus Pierre; Bardeesy Nabeel; Bartholin Laurent^*

来源：American Journal Of Pathology, 2012, 180(6): 2214-2221.

DOI：10.1016/j.ajpath.2012.02.006

Transcriptional intermediary factor 1 gamma (TIF1 gamma; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripotency, embryonic development, and tumor suppression. TIF1 gamma expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1 gamma inactivation cooperates with the Kras(G12D) oncogene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-Kras(G12D); Tif1 gamma(lox/lox) mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1 gamma tumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4 (deleted in pancreatic carcinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1 gamma and Smad4 signaling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1 gamma(lox/lox) (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1 gamma tumor-suppressor effects during progression from a premalignant to a malignant state in our mouse model of pancreatic cancer are independent of Smad4. These findings establish, for the first time to our knowledge, that Tif1 gamma and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs. (Am J Pathol 2012, 180:2214-2221; http://dx.doi.org/10.1016/j.ajpath.2012.02.006)

• 出版日期2012-6