Author information
1
Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
2
Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
3
Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
4
Monash University Department of Surgery, Alfred Hospital, Melbourne, VIC 3004, Australia.
5
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
6
Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Monash Bioinformations Platform, Monash University, Clayton, VIC 3800, Australia.
7
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
8
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Kazusa DNA Research Institute Kisarazu, Chiba 292-0818, Japan.
9
Anatomical Pathology, Alfred Hospital, Prahran, VIC 3004, Australia.
10
Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. Electronic address: tony.tiganis@monash.edu.
Abstract
Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.