title: Tif1γ suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway.
abstract: Transcriptional intermediary factor 1γ (TIF1γ; 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. TIF1γ expression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1γ 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); Tif1γ(lox/lox) mice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1γ 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 Tif1γ and Smad4 signaling in pancreatic tumors and found that Pdx1-Cre; LSL-Kras(G12D); Smad4(lox/lox); Tif1γ(lox/lox) (alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1γ 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 Tif1γ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France.
authors.forename: David F
authors.initials: DF
authors.lastname: Vincent
authors.forename: Johann
authors.initials: J
authors.lastname: Gout
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chuvin
authors.forename: Vanessa
authors.initials: V
authors.lastname: Arfi
authors.forename: Roxane M
authors.initials: RM
authors.lastname: Pommier
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jonckheere
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.forename: Bastien
authors.initials: B
authors.lastname: Kaniewski
authors.forename: Sylvie
authors.initials: S
authors.lastname: Martel
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Langlois
authors.forename: Sophie
authors.initials: S
authors.lastname: Goddard-Léon
authors.forename: Amélie
authors.initials: A
authors.lastname: Colombe
authors.forename: Marc
authors.initials: M
authors.lastname: Janier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Valcourt
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D008279:Magnetic Resonance Imaging; D051379:Mice; D008817:Mice, Mutant Strains; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D014157:Transcription Factors; C491420:Trim33 protein, mouse