Tif1γ Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue American Journal of Pathology Année : 2012

Tif1γ Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway

David Vincent
Nabeel Bardeesy

Résumé

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.

Domaines

Cancer
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Dates et versions

hal-02954464 , version 1 (01-10-2020)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

David Vincent, Johann Gout, Nicolas Chuvin, Vanessa Arfi, Roxane M. Pommier, et al.. Tif1γ Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway. American Journal of Pathology, 2012, 180 (6), pp.2214-2221. ⟨10.1016/j.ajpath.2012.02.006⟩. ⟨hal-02954464⟩
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