Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice

Sally Yu Shi, Cynthia T. Luk, Stephanie A. Schroer, Min Jeong Kim, David W. Dodington, Tharini Sivasubramaniyam, Lauren Lin, Erica P. Cai, Shun Yan Lu, Kay-Uwe Wagner, Richard P. Bazinet, Minna Woo

Research output: Contribution to journalArticle

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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 steatosis per se promotes 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 (LJAK2 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 KOmice 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.

Original languageEnglish (US)
Pages (from-to)3789-3799
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number9
DOIs
StatePublished - Mar 3 2017

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Janus Kinase 2
Hepatocellular Carcinoma
Liver
Fatty Liver
Janus Kinases
Hepatocytes
Transcription
Inflammation
Transducers
Signal transduction
Critical Pathways
Liver Neoplasms
Choline
Methionine
Carcinogens
Disease Progression
Tumors
Signal Transduction
Carcinogenesis
Apoptosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shi, S. Y., Luk, C. T., Schroer, S. A., Kim, M. J., Dodington, D. W., Sivasubramaniyam, T., ... Woo, M. (2017). Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice. Journal of Biological Chemistry, 292(9), 3789-3799. https://doi.org/10.1074/jbc.M116.752519

Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice. / Shi, Sally Yu; Luk, Cynthia T.; Schroer, Stephanie A.; Kim, Min Jeong; Dodington, David W.; Sivasubramaniyam, Tharini; Lin, Lauren; Cai, Erica P.; Lu, Shun Yan; Wagner, Kay-Uwe; Bazinet, Richard P.; Woo, Minna.

In: Journal of Biological Chemistry, Vol. 292, No. 9, 03.03.2017, p. 3789-3799.

Research output: Contribution to journalArticle

Shi, SY, Luk, CT, Schroer, SA, Kim, MJ, Dodington, DW, Sivasubramaniyam, T, Lin, L, Cai, EP, Lu, SY, Wagner, K-U, Bazinet, RP & Woo, M 2017, 'Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice', Journal of Biological Chemistry, vol. 292, no. 9, pp. 3789-3799. https://doi.org/10.1074/jbc.M116.752519
Shi SY, Luk CT, Schroer SA, Kim MJ, Dodington DW, Sivasubramaniyam T et al. Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice. Journal of Biological Chemistry. 2017 Mar 3;292(9):3789-3799. https://doi.org/10.1074/jbc.M116.752519
Shi, Sally Yu ; Luk, Cynthia T. ; Schroer, Stephanie A. ; Kim, Min Jeong ; Dodington, David W. ; Sivasubramaniyam, Tharini ; Lin, Lauren ; Cai, Erica P. ; Lu, Shun Yan ; Wagner, Kay-Uwe ; Bazinet, Richard P. ; Woo, Minna. / Janus Kinase 2 (JAK2) dissociates hepatosteatosis from hepatocellular carcinoma in mice. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 9. pp. 3789-3799.
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AU - Shi, Sally Yu

AU - Luk, Cynthia T.

AU - Schroer, Stephanie A.

AU - Kim, Min Jeong

AU - Dodington, David W.

AU - Sivasubramaniyam, Tharini

AU - Lin, Lauren

AU - Cai, Erica P.

AU - Lu, Shun Yan

AU - Wagner, Kay-Uwe

AU - Bazinet, Richard P.

AU - Woo, Minna

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