title: Critical cholangiocarcinogenesis control by cryptochrome clock genes.
abstract: A coordinated network of molecular circadian clocks in individual cells generates 24-hr rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. As divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1-/-Cry2-/-mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST and ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology. Five months after initiation of DEN treatment, we found that Cry1-/-Cry2-/-mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1-/-Cry2-/-mice as compared to WT mice (p = 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly eightfold increase in the average number of cholangiocarcinomas in Cry1-/-Cry2-/-mice, as compared to WT mice. This study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically induced liver carcinogenesis. In addition, the pronounced shift toward cholangiocarcinoma in DEN exposed Cry1-/-Cry2-/-mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis.
authors.affiliation: INSERM and Paris Sud university, UMRS 935, Team "Cancer Chronotherapy and Postoperative Liver", Campus CNRS, Villejuif, F-94807, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Mteyrek
authors.affiliation: INSERM and Paris Sud university, UMRS 935, Team "Cancer Chronotherapy and Postoperative Liver", Campus CNRS, Villejuif, F-94807, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.affiliation: Department of Medical Oncology and Laboratory of Anatomy and Pathological Cytology, Hôpital Paul Brousse, Assistance Publique-Hopitaux de Paris, Villejuif, F-94800, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Oklejewicz
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: Department of Pharmacology, Istanbul University Faculty of Pharmacy, Beyazit, Istanbul, TR-34116, Turkey.
authors.forename: Alper
authors.initials: A
authors.lastname: Okyar
authors.affiliation: INSERM and Paris Sud university, UMRS 935, Team "Cancer Chronotherapy and Postoperative Liver", Campus CNRS, Villejuif, F-94807, France.|Department of Medical Oncology and Laboratory of Anatomy and Pathological Cytology, Hôpital Paul Brousse, Assistance Publique-Hopitaux de Paris, Villejuif, F-94800, France.|Warwick Medical School, Cancer Chronotherapy Unit, Coventry, CV4 7AL, United Kingdom.
authors.forename: Francis
authors.identifier: 0000-0003-1364-7463
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000410:Alanine Transaminase / Q000235:genetics; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology*; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics
chemical_list: D056931:Cryptochromes; D000410:Alanine Transaminase
keywords: Cry1 and Cry2 genes; cholangiocarcinoma; circadian rhythm; liver carcinogenesis; mouse