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 (ER) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ER 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 ER 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. What's new? More men than women get liver cancer, in part because of the protective effect of the estrogen pathway. Many women who do develop hepatocellular cancer have less estrogen receptor due to higher levels of miR-18a, which slows estrogen receptor production. In this paper, the authors asked, what causes the increase in miR-18a? They found that p53 participates in pumping out miR-18a, and further investigation revealed that tying up p53 decreased levels of miR-18a, while overexpressing p53 increased miR-18a. Samples taken from female HCC patients confirmed this association, suggesting that p53 could be a useful therapeutic target in female HCC.