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

Abstract

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 (ERa) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ERa 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 ERa 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.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and its strong association with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is well known.1 Among the nonviral risk factors, the male sex factor has long been considered as a major risk factor of HCC, 2,3 as the incidence of HCC in male patients is 2-to 11-fold higher than that observed in females; this is even more evident in HBV-related HCC. 4 The sex hormones, including both the androgen and estrogen axes, are involved in the regulation of this gender difference in HCC. 4,5 The serial cohort studies performed by Yu et al. showed that an elevation in the activity of the androgen pathway was associated with higher HCC risk in male HBV carriers, whereas an elevation in the activity of the estrogen pathway was associated with lower HCC risk in female HBV carriers. 6 These results suggested opposite roles of the androgen and estrogen pathways in hepatocarcinogenesis, which might contribute to the gender difference of HCC.At the molecular level, recent studies have identified several mechanisms underlying the function of androgen and estrogen in the hepatocarcinogenic process. Regarding the androgen pathway, we found a positive regulatory loop between the viral Hepatitis B virus X protein and ligandactivated androgen receptor (AR) transcriptional activation in HBV-infected hepatocytes. This loop leads to persistently elevated AR activity and increased HBV mRNA transcription, which contribute to the ...

MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5

“…MiR-18a has shown different expression levels in different tumors. Previous studies have reported that miR-18a was highly expressed and exerted an oncogenic role across a wide spectrum of human solid cancers [25][26][27]. However, miR-18a expression was not changed compared with that of control K562 cells for reasons yet to be clarified, despite other members of the miR-17-92 cluster being upregulated in lentivirally transduced K562 clones [28].…”

MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis

“…It is of great interest that miR-130a expression level was high in most female HCC patients. Till now, few miRNAs have been found to be correlated with sex [32,33]. Before the detailed function of miR-130a in female HCC patients is studied, the expression results are still needed to be confirmed in more female patients.…”

MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1α

“…miR-18a belongs to the miR17-92 gene cluster, of which HIF-1α is a target gene (16). It has been reported that miR-18a serves a crucial function in the occurrence and development of myocardial ischemia (17), colonic neoplasm (18), liver tumors (19), prostate cancer (20) and malignant gliomas (21). Furthermore, a previous study suggests that miR-18a may be a specific biomarker for the early diagnosis and treatment of tumors (22).…”