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Genomic loss of miR-486 regulates tumor progression and the OLFM4 antiapoptotic factor in gastric cancer.

 Hue-Kian Oh  ;  Angie Lay-Keng Tan  ;  Kakoli Das  ;  Chia-Huey Ooi  ;  Nian-Tao Deng  ;  , Iain BeeHuat Tan  ;  Emmanuel Beillard  ;  Julian Lee  ;  Kalpana Ramnarayanan  ;  Sun-Young Rha 
 CLINICAL CANCER RESEARCH, Vol.17(9) : 2657-2667, 2011 
Journal Title
Issue Date
Apoptosis/genetics ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Carcinoma/genetics* ; Carcinoma/pathology ; Cell Line, Tumor ; Cell Proliferation ; Disease Progression ; Gene Deletion* ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Genomic Instability/genetics ; Genomic Instability/physiology ; Granulocyte Colony-Stimulating Factor/genetics* ; Granulocyte Colony-Stimulating Factor/metabolism ; Humans ; MicroRNAs/genetics ; MicroRNAs/physiology* ; Microarray Analysis ; Neoplasms/genetics ; Neoplasms/pathology ; Stomach Neoplasms/genetics* ; Stomach Neoplasms/pathology
PURPOSE: MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC). EXPERIMENTAL DESIGN: Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors. RESULTS: Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target. Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 3' untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing. CONCLUSIONS: miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
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