Obesity is a risk factor for a range of cancers, with the association being particularly strong for hepatocellular carcinoma (HCC). Although it was thought that nonalcoholic steatohepatitis (NASH) and fibrosis or cirrhosis were required for the development of HCC, new research suggests that obesity can cause HCC independently of NASH and fibrosis.

Signal transducer and activator of transcription (STAT) signalling pathways are known to be involved in the development of HCC. In mice, the researchers demonstrated that hepatic STAT1 and STAT3 signalling were increased in conditions of obesity. Furthermore, STAT1 signalling was elevated in the livers of mice fed a nonalcoholic fatty liver (NAFL)-promoting diet high in fat, and was further elevated in the livers of mice fed a NASH-promoting diet. These findings were supported by human studies; STAT1 signalling was increased in patients with obesity and nonalcoholic fatty liver disease (NAFLD).

In addition, the STAT1 phosphatase TCPTP was found to be oxidized in the livers of mice fed a NAFL-promoting diet (and the oxidation was further increased in mice fed a NASH-promoting diet) and in the livers of patients with obesity and NAFLD. In mice that were deficient in TCPTP, STAT1 signalling was increased in liver cells, which led to accumulation of T cells, inflammation, NASH and fibrosis when the mice were fed a high-fat diet. By contrast, wild-type mice developed steatosis, but not fibrosis and NASH, when fed a high-fat diet.

When STAT1 signalling was reduced in TCPTP-deficient mice fed a high-fat diet, T cell recruitment was prevented and NASH and fibrosis did not develop; however, the mice did develop HCC. The authors suggest that obesity and STAT3 signalling are important for the development of HCC, as chow-fed mice did not develop HCC and reducing STAT3 signalling prevented the development of HCC.

increased STAT3 signalling … is sufficient to drive the development of HCC

The authors conclude that increased STAT3 signalling in conditions of obesity and NAFLD is sufficient to drive the development of HCC, even in the absence of fibrosis or cirrhosis. They suggest that it is the oxidative and inflammatory environment of the liver in NAFLD that results in HCC, rather than the development of NASH or fibrosis.