0 avis
Tif1γ Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway
Archive ouverte
Edité par CCSD ; American Society for Investigative Pathology / Elsevier -
International audience. Transcriptional intermediary factor 1␥ (TIF1␥; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripo-tency, embryonic development, and tumor suppression. TIF1␥ expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1␥ inactivation cooperates with the Kras G12D onco-gene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-Kras G12D ; Tif1␥ lox/lox mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1␥ tumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4 (deleted in pancreatic car-cinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1␥ and Smad4 sig-naling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras G12D ; Smad4 lox/lox ; Tif1␥ lox/lox (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1␥ 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␥ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.
Consulter en ligne
Suggestions
Du même auteur
