We investigated expression profiles of microRNA (miRNA) in gastric carcinomas by use of a miRNA microarray platform covering a total of 470 human miRNAs. We identified 39 differentially expressed miRNAs in gastric carcinoma, of which six were significantly downregulated and the other 33 were upregulated. We found that miRNA−375 (miR−375) was the most downregulated and that its ectopic expression in gastric carcinoma cells markedly reduced cell viability via the caspase−mediated apoptosis pathway. Interestingly, we found that expression of miR−375 inhibited expression of PDK1, which is a direct target of miR−375, followed by suppression of Akt phosphorylation. Further analysis by gene expression microarray revealed that 14−3−3zeta, a potent antiapoptotic gene, was significantly downregulated at both the mRNA and protein levels in cells transfected with miR−375. The activity of a luciferase reporter containing the miR−375 binding sequence at the 3' untranslated region (UTR) of 14−3−3zeta mRNA was repressed by the ectopic expression of miR−375, suggesting that miR−375 targets the 3' UTR of 14−3−3zeta. In addition, knockdown of either PDK1 or 14−3−3zeta in gastric carcinoma cells induced caspase activation, which was also observed in miR−375−transfected cells, suggesting that miR−375 may exert its proapoptotic function, at least in part, through the downregulation of PDK1 and 14−3−3zeta. Taken together, we propose that miR−375 is a candidate tumor suppressor miRNA in gastric carcinoma. Cancer Res; 70(6); 2339−49.

PMID: 20215506 [PubMed − as supplied by publisher] Source: National Library of Medicine.