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Androgen pathway stimulates MicroRNA‐216a transcription to suppress the tumor suppressor in lung cancer‐1 gene in early hepatocarcinogenesis
Author(s) -
Chen PoJen,
Yeh ShiouHwei,
Liu WanHsin,
Lin ChenChing,
Huang HsuanCheng,
Chen ChiLing,
Chen DingShinn,
Chen PeiJer
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25695
Subject(s) - microrna , androgen receptor , cancer research , carcinogenesis , hbx , biology , androgen , prostate cancer , messenger rna , medicine , cancer , endocrinology , transfection , gene , genetics , hormone
Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC‐related miRNAs between precancerous and cancerous liver tissues, we found miR‐216a and miR‐224 were significantly up‐regulated, starting from the precancerous stage. Furthermore, the elevation of miR‐216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri‐miR‐216a is activated transcriptionally by the androgen pathway in a ligand‐dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri‐miR‐216a was delineated, and one putative androgen‐responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri‐miR‐216a by the androgen pathway. One target of miR‐216a was shown to be the tumor suppressor in lung cancer‐1 gene ( TSLC1 ) messenger RNA (mRNA) through the three target sites at its 3′ untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR‐216a but a decrease of TSLC1. Conclusion: The current study discovered the up‐regulation of miRNA‐216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (H EPATOLOGY 2012)