Elevated p53 promotes the processing of miR‐18a to decrease estrogen receptor‐α in female hepatocellular carcinoma

The estrogen pathway has long been implicated as a tumor protector in female hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Our previous study identified that estrogen receptor alpha (ERα) protein is downregulated in 60% of female HCC cases, via a miR‐18a elevation mediated suppression of ERα translation. This study aims to delineate the mechanism underlying the upregulation of miR‐18a in female HCC. The analysis of 77 female HCC specimens revealed that miR‐18a levels were associated with pre‐miR‐18a rather than pri‐miR‐18a levels, suggesting an enhanced processing of pri‐ to pre‐miR‐18a. Among a panel of factors involved in microRNA processing, p53 was identified as a novel regulator for miR‐18a maturation process. Knockdown of p53 by si‐RNA decreased the level of miR‐18a, whereas overexpression of either wild‐type or mutant p53 increased its level. The association between the elevation of miR‐18a and the accumulation of p53, mainly caused by somatic mutations, was confirmed in the clinical specimens of HBV‐related female HCC. By analyzing the association with clinicopathological features, activation of this p53/miR‐18a pathway mainly occurs in younger or noncirrhosis female HCC patients and associated with a trend of worse overall survival. Therefore, this study demonstrated a novel function of elevated/mutant p53 in regulating the amount of ERα protein through its promoting the biogenesis of miR‐18a, which could lead to decrease the tumor‐protective function of the estrogen pathway in female hepatocarcinogenesis.