Modulatory effect of euxanthone in liver cancer-bearing obese mice: crosstalk between PPARγ and TIMP3 signalling axes.

ABSTRACT

Liver cancer is one of the prominent cancer-associated fatal diseases with > 80% of cases befall in low-middle resource nations worldwide. In the current study, we studied the effect of euxanthone (EUX) on obesity-associated liver cancer using a high-fat diet-fed mouse model of diethylnitrosamine (DEN)-provoked hepatocellular carcinoma. Mice with 2 weeks of age were intraperitoneally injected with diethylnitrosamine (DEN) 25 mg/kg b.w. After 4 weeks, the mice were divided into four groups with low-fat diet (LFD), high-fat diet (HFD), and EUX treatment groups with or without PPARγ inhibitor (GW9662). We observed that TIMP3, E-cadherin, and Klotho expressions were downmodulated, while MMP9, ADAM17, and Wnt signalling biofactors (Wnt5a, Wnt3a and ß-catenin) were upmodulated in the HFD groups. Nevertheless, these aberrations were reciprocated by the treatment with EUX; at the same time, co-administration of PPARγ inhibitor ablated the anti-cancer effects of EUX, indicating that PPARγ activation is a pivotal mechanism underpinning the negative regulation of oncogenic factors by EUX. Together, these results imply that EUX might be a viable therapeutic option in the treatment of obesity-associated hepatocarcinogenesis.