title: Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Po-Jen
authors.initials: PJ
authors.lastname: Chen
authors.forename: Shiou-Hwei
authors.initials: SH
authors.lastname: Yeh
authors.forename: Wan-Hsin
authors.initials: WH
authors.lastname: Liu
authors.forename: Chen-Ching
authors.initials: CC
authors.lastname: Lin
authors.forename: Hsuan-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
mesh_terms: D000728:Androgens / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012737:Sex Factors; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D000728:Androgens; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C575482:MIRN216 microRNA, human; C546140:MIRN224 microRNA, human; D035683:MicroRNAs