miR-22 Promotes HBV-Related Hepatocellular Carcinoma Development in Males

Purpose: Previous reports have shown that IL-1α–MyD88–IL-6 signaling is essential in promoting hepatocellular carcinoma (HCC) development in a diethylnitrosamine (DEN)-induced mouse model. We aimed to determine whether interleukin (IL)-1α regulates HCC development in humans. Methods: HBV-associated HCC tissue, corresponding adjacent tissue, and normal tissue samples were obtained from 80 male and 36 female patients. IL-1α, ERα, IL-6, and MyD88 were quantified by using real-time PCR and Western blot. Stem-loop PCR was used to quantify miR-22 expression. Luciferase reporter assays were used to study transcriptional regulation. Results: IL-1α was highly expressed in male tumor adjacent tissue compared with normal tissue ( P = 0.025); however, this was not the case for female subjects. A linear relationship was observed between increased IL-1α and decreased ERα expression in male tumor adjacent tissue ( r = −0.616, P = 0.004). Our results also indicated that estrogen (E2) was suppressed upon IL-1α secretion in ERα-overexpressed HCC cells. We detected high expression of miR-22 in male tumor adjacent tissue compared with controls ( P = 0.027); furthermore, we showed that miR-22 downregulates ERα transcription by targeting the 3′-untranslated region. In the DEN-induced model, IL-1α was highly expressed in sprouting tumors and gradually decreased in conjunction with HCC development. Conclusion: Overexpression of miR-22 in male tumor adjacent tissue was associated with downregulated ERα expression, potentially by attenuating the protective effect of estrogen and causing increased IL-1α expression. These results may explain the high incidence of HBV-associated HCC in the male population. Clin Cancer Res; 17(17); 5593–603. ©2011 AACR .