title: Oxidative stress induced by inactivation of TP53INP1 cooperates with KrasG12D to initiate and promote pancreatic carcinogenesis in the murine pancreas.
abstract: Tumor protein p53-induced nuclear protein 1 (TP53INP1) is involved in cell stress response. Its expression is lost at the pancreatic intraepithelial neoplasia 1b (PanIN1b)/PanIN2 stage of pancreatic carcinogenesis. Our objective was to determine whether TP53INP1 loss of expression contributes to pancreatic cancer formation in a conditional KrasG12D mouse model. We generated Kras-INP1KO mice using LSL-Kras(G12D/+);Pdx1-Cre(+/-) mice (Kras mice) and TP53INP1(-/-) mice. Analysis of pancreases during ageing shows that in the presence of activated Kras, TP53INP1 loss of expression accelerated PanIN formation and increased pancreatic injury and the number of high-grade lesions as compared with what occurs in Kras mice. Moreover, cystic lesions resembling intraductal papillary mucinous neoplasm (IPMN) were observed as early as 2 months of age. Remarkably, TP53INP1 is down-regulated in human IPMN. Activation of the small GTPase Rac1 shows that more oxidative stress is generated in Kras-INP1KO than in Kras mice pancreas despite elevated levels of the Nrf2 antioxidant regulator. We firmly establish the link between Kras-INP1KO pancreatic phenotype and oxidative stress with rescue of the phenotype by the antioxidant action of N-acetylcysteine. Our data provide in vivo functional demonstration that TP53INP1 deficiency accelerates progression of pancreatic cancer, underlining its role in the occurrence of IPMN and highlighting the importance of TP53INP1 in the control of oxidative status during development of pancreatic cancer.
authors.affiliation: Histology Facility, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France.
authors.forename: Talal
authors.initials: T
authors.lastname: Al Saati
authors.forename: Pascal
authors.initials: P
authors.lastname: Clerc
authors.forename: Naïma
authors.initials: N
authors.lastname: Hanoun
authors.forename: Sylvain
authors.initials: S
authors.lastname: Peuget
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.forename: Véronique
authors.initials: V
authors.lastname: Gigoux
authors.forename: Florence
authors.initials: F
authors.lastname: Capilla
authors.forename: Benoît
authors.initials: B
authors.lastname: Béluchon
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.forename: Louis
authors.initials: L
authors.lastname: Buscail
authors.forename: Alice
authors.initials: A
authors.lastname: Carrier
authors.forename: Nelson
authors.initials: N
authors.lastname: Dusetti
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; C518507:tumor protein 53-induced nuclear protein 1, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)