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

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• 作者：Chiao-Ling Li ; Kun-Huei Yeh ; Wan-Hsin Liu ; Chi-Ling Chen ; Ding-Shinn Chen ; Pei-Jer Chen and Shiou-Hwei Yeh
• 关键词：estrogen ; gender ; hepatitis B virus ; hepatocellular carcinoma ; microRNA ; p53
• 刊名：International Journal of Cancer
• 出版年：2015
• 出版时间：15 February, 2015
• 年：2015
• 卷：136
• 期：4
• 页码：761-770
• 全文大小：632K
• ISSN：1097-0215

文摘

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.