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 (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.

• Authors: Chiao-Ling Li, Kun-Huei Yeh, Wan-Hsin Liu, Chi-Ling Chen, Ding-Shinn Chen, Pei-Jer Chen, Shiou-Hwei Yeh
• Journal: International journal of cancer (Int J Cancer) Vol. 136 Issue 4 Pg. 761-70 (Feb 15 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 24975878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• MIRN18 microRNA, human
• MicroRNAs
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Adult
• Aged
• Carcinoma, Hepatocellular (genetics, metabolism)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (genetics, metabolism)
• Male
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Mutation
• RNA Interference
• RNA Processing, Post-Transcriptional
• Sex Characteristics
• Tumor Suppressor Protein p53 (genetics, metabolism)