Inhibitory effects of resveratrol on hepatitis B virus X-protein (HBx)-induced hepatocellular carcinoma (HCC)

Abstract

Liver cancer occurs very frequently worldwide and hepatocellular carcinoma (HCC) accounts for more than 80% of total primary liver cancer cases. Here, the anticarcinogenic effects of resveratrol against hepatitis B virus (HBV)-induced HCC were investigated using HBV X-protein-overexpressing Huh7 (Huh7-HBx) human hepatoma cells. MTT assay showed that resveratrol decreased cell viability. Fluorescence-activated cell sorter analysis showed that it induced G1 cell cycle arrest without increasing the sub-G1 phase cell population. Therefore, we evaluated its effect on regulation of cyclin D1, which is critically involved in G1/S transition. Resveratrol lowered cyclin D1 transcription. Western blot analysis of the effects of resveratrol on upstream cyclin D1 transcriptional signaling, extracellular signal-related kinase (ERK), p90RSK, Akt, and p70S6K revealed inhibition of Akt but not ERK signaling pathways. Collectively, these results indicated that resveratrol inhibits Huh7-HBx proliferation by decreasing cyclin D1 expression through blockade of Akt signaling. We investigated the anti-carcinogenic effect and mechanism of resveratrol in xenograft model mice implanted with Huh7-HBx cells. Intraperitoneal injection of resveratrol reduced the tumor size in the mice. Expression of survivin was reduced, whereas cyclin D1 was not affected. These results demonstrated that treatment with resveratrol might be helpful to manage of HBV-induced HCC by regulating survivin.