MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells.

BACKGROUND & AIMS: Men have a higher incidence of hepatocellular carcinoma (HCC) than women, which is believed to partly be because of protective effects of estrogen. We sought to determine whether there were differences in levels of microRNA (miRNA) molecules between male and female HCC samples.

METHODS: The expression profiles of a panel of candidate miRNAs were compared between male and female HCC tissues using the TaqMan miRNA assay. A luciferase reporter assay was used to identify mRNA targets recognized by specific miRNAs. The levels of pri- and pre-miRNA for each specific miRNA were assayed by quantitative reverse-transcription polymerase chain reaction to delineate the step deregulated in the biogenesis process. Finally, a colorimetric assay was used to determine the effect of specific miRNAs on hepatoma cell proliferation.

RESULTS: The miR-18a miRNA increased specifically in samples from female HCC patients (female/male ratio, 4.58; P = .0023). The gene ESR1, which encodes the estrogen receptor-alpha (ERalpha), was identified as a target of miR-18a. miR-18a can repress ERalpha translation by binding to its mRNA at the 3' untranslated region. Increased levels of miR-18a in female HCC tissues correlated with reduced ERalpha expression; the level of pre-miR-18a changed in concordance with that of mature miR-18a in these tissues. Overexpression of miR-18a decreased ERalpha levels but stimulated the proliferation of hepatoma cells.

CONCLUSIONS: This study provides a novel miRNA-mediated regulatory mechanism for controlling ERalpha expression in hepatocytes. miR-18a prevents translation of ERalpha, potentially blocking the protective effects of estrogen and promoting the development of HCC in women.