Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is refractory to nearly all available therapies with a 5 year survival rate of < 9%. Over the last 20 years, the incidence of HCC in economically developed countries has been increasing; HCC has nearly doubled in the US. The obesity epidemic accounts for as much as 50% of the increase in HCC in developed nations.
The impact of obesity and type 2 diabetes on HCC is thought to be due to the increased risk for non-alcoholic fatty liver disease (NAFLD) and the progression to non-alcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease characterised by chronic inflammation and fibrosis. The causes for the progression to NASH and HCC development in obesity remain unclear.
Inflammation and oxidative stress occur in the liver in obesity/type 2 diabetes and reactive oxygen species (ROS) such as H2O2 can oxidise and inactivate protein tyrosine phosphatases (PTPs) for the promotion of tyrosine phosphorylation-dependent signaling.
We reported previously that obesity-associated oxidative stress drives the oxidation and inactivation of PTPs such as TCPTP and PTP1B in the liver to promote STAT-1/3 signaling [1].
I will present data for ROS inactivating PTPs to promote STAT-1/3 signalling and the development of NASH and HCC in obesity.
The results presented will define hepatic PTP oxidation/inactivation as a key mechanism for obesity-mediated NASH and HCC.