Timp3 deficiency affects the progression of DEN-related hepatocellular carcinoma during diet-induced obesity in mice.

Abstract

Obesity and low-grade inflammation are associated with an increased risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The tissue inhibitor of metalloproteinase (TIMP) 3, an endogenous inhibitor of protease activity that represents a key mediator of inflammation, is reduced in inflammatory metabolic disorders and cancer. In contrast, Timp3-deficient mice (Timp3-/-) are highly resistant to developing HCC in response to a diethylnitrosamine (DEN); therefore, we aimed to elucidate the biological role of genetic loss of Timp3 in obesity-related hepatocarcinogenesis. Fourteen-day-old male wild-type (wt) and Timp3-/- mice were injected with 25mg/kg DEN or an equal volume of saline. After 4weeks, mice were randomized into two dietary groups and fed either normal or high-fat diet and allowed to grow until 32weeks of age. Liver histological features were analyzed, and differentially expressed genes in the liver were quantified. In Timp3-/- mice fed with the obesogenic diet, despite the increase in liver steatosis and inflammation, both the number of tumors and the total tumor size are significantly reduced 30weeks post-DEN injection, compared to control mice. Moreover, Timp3 deletion in hepatocarcinogenesis during obesity is associated with a reduction in FoxM1 transcriptional activity through H19/miR-675/p53 pathway. This study suggests that Timp3 ablation leads to cell cycle perturbation, at least in part by repressing FoxM1 transcriptional activity through H19/miR-675/p53 pathway.