Ginsenoside Rh2 Targets EGFR by Up-Regulation of miR-491 to Enhance Anti-tumor Activity in Hepatitis B Virus-Related Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors in humans. The typical therapeutic strategies include a combination of chemotherapy, radiotherapy, and surgery, whereas the survival rate of patients is very poor. Ginsenoside Rh2 has been reported to have therapeutic effects on some tumors, but its effect on HCC has not been extensively evaluated. Here, we show that ginsenoside Rh2 can effectively inhibit the proliferation and cell survival of HCC cells in vitro and in a mouse model. Moreover, the inhibition of the tumor growth appears to result from combined effects on decreased tumor cell proliferation and cell viability. Further analyses suggest that ginsenoside Rh2 may have its anti-tumor effect through inhibition of epidermal growth factor receptor (EGFR) signaling pathway. Recombinant EGFR was given together with ginsenoside Rh2 to the tumor cells, which completely blocked the anti-tumor effect of ginsenoside Rh2. Our data also show that miR-491 is up-regulated in SMMC-7721 cells after Rh2 treatment. There is a negative correlation between EGFR and miR-491 levels in SMMC-7721 cells and miR-491 directly targeted EGFR at translational level. Our data not only reveal an anti-tumor effect of ginsenoside Rh2 but also demonstrate that this effect may function via activation and inhibition of EGFR signaling in HCC cells. The results suggest miR-491 can be a promising regulatory factor in EGFR signal transduction.

Keywords: EGFR; Ginsenoside Rh2; Hepatitis B virus; Hepatocellular carcinoma; miR-491.