Obesity-induced hepatic STAT3 signaling drives hepatocellular carcinoma (HCC) independent of fibrosis.

  • Major finding: Obesity-induced hepatic STAT3 signaling drives hepatocellular carcinoma (HCC) independent of fibrosis.

  • Concept: Obesity promotes hepatic STAT1 signaling that drives T-cell infiltration, NASH, and fibrosis.

  • Impact: The oxidative hepatic environment in obesity promotes HCC independent of NASH and fibrosis.

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Obesity can drive hepatocellular carcinoma (HCC), and obesity-associated tumorigenesis has been thought to develop via nonalcoholic fatty liver disease (NAFLD) that progresses to nonalcoholic steatohepatitis (NASH), which is characterized by inflammation that results in fibrosis and cirrhosis, and ultimately to HCC. However, the underlying mechanism remains unclear, and HCC can develop in obese patients without NASH. Protein tyrosine phosphatases (PTP) can be extensively oxidized in the livers of high-fat-fed mice that develop NAFLD, prompting Grohmann, Wiede, and colleagues to investigate the role of PTP oxidation in NAFLD and HCC. Several PTPs, including T-cell PTP (TCPTP), were increased in the livers of patients with NAFLD, and in the livers of mice fed a high-fat diet. Inactivation of TCPTP in the liver promoted NASH, fibrosis, and HCC in obese mice. STAT1 and STAT3 are direct targets of TCPTP, and RNA sequencing revealed that TCPTP inactivation resulted in upregulation of STAT1/3 target genes, and these genes were also upregulated in patients with NAFLD. Mechanistically, TCPTP inactivation induced NASH in a STAT1 dependent manner, promoting inflammation, T-cell recruitment, and fibrosis. In contrast, TCPTP inactivation induced inflammation and HCC in a STAT3 dependent manner. STAT3-mediated HCC occurred independently of T-cell recruitment, NASH, and fibrosis. Further, TCPTP deletion enhanced the growth of established HCC xenografts and resulted in increased STAT3 phosphorylation. Taken together, these findings indicate that obesity independently drives NASH and HCC via distinct STAT1- and STAT3-dependent mechanisms, insights that might guide therapeutic development for liver cancer versus liver disease.

Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T, et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 2018 Oct 25 [Epub ahead of print].

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.