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ERα36 is an effective target of epigallocatechin-3-gallate in hepatocellular carcinoma.

Epigallocatechin-3-gallate (EGCG) is a natural product with potential anti-cancer property whose direct target has not been identified. This study intended to investigate ERα36, a new isoform of estrogen receptor alpha (ERa), as a therapeutic target of EGCG in hepatocellular carcinoma (HCC). In this work, we examined the expression level of ERs in HCC cell lines and a normal human liver cell line, and evaluated inhibition effect of EGCG on these cells in vitro, and further on Hep3B in vivo. The results showed that ERα36 was the main ER in HCC cells and served as a biomarker of responsiveness to EGCG inhibition, and there was a positive correlation between ERα36 expression level and inhibitory effect of EGCG as indicated by IC50. In vivo experiments also showed dose-dependent inhibition of EGCG on ERα36 high-expressing Hep3B. EGCG exerted inhibition on Hep3B cells by both anti-proliferation and pro-apoptosis. ERα36-EGFR-Her-2 feedback loop, PI3K/Akt and MAPK/ERK pathways were inhibited, while caspase 3 was activated by EGCG in Hep3B cells, with p-ERK accumulated in cytoplasm. The inhibitory effect of EGCG was significantly attenuated when ERα36 was pre-activated. This is the first evidence that EGCG exerts its anti-cancer effect by inhibiting ERα36, followed with inhibition of the ERα36-EGFR-Her-2 feedback loop and PI3K/Akt, MAPK/ERK pathway, activation of caspase 3, and accumulation of p-ERK in cytoplasm. It suggests that ERα36 might be an efficient target of EGCG in HCC.