title: Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.
abstract: Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosisper sepromotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline-deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma.
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.|the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.|the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.|the Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodington
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.|the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tharini
authors.initials: T
authors.lastname: Sivasubramaniyam
authors.affiliation: the Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Lin
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.|the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Shun-Yan
authors.initials: SY
authors.lastname: Lu
authors.affiliation: the Eppley Institute for Research in Cancer and Allied Diseases and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, and.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: the Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
authors.affiliation: From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada, mwoo@uhnresearch.ca.|the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|the Division of Endocrinology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D005234:Fatty Liver / Q000378:metabolism; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: Janus kinase (JAK); cell death; cell proliferation; diethylnitrosamine; hepatocellular carcinoma; inflammation; mouse; non-alcoholic fatty liver disease