title: MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis.
abstract: BACKGROUND
  MicroRNA (miRNA, miR)-18a is a member of the miR-17-92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17-92 cluster and its individual miRNAs are largely unknown.
  
  
  RESULTS
  In this study, we investigated the expression of the miR-17-92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc.
  
  
  CONCLUSIONS
  Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.
authors: Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors: W
authors: W
authors: Wu
authors: M
authors: M
authors: Takanashi
authors: N
authors: N
authors: Borjigin
authors: S-i
authors: SI
authors: Ohno
authors: K
authors: K
authors: Fujita
authors: S
authors: S
authors: Hoshino
authors: Y
authors: Y
authors: Osaka
authors: A
authors: A
authors: Tsuchida
authors: M
authors: M
authors: Kuroda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C522576:MIRN18A microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human