The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers

MicroRNAs (miRNA/miR) are a class of small noncoding RNAs implicated in the pathogenesis of various malignancies. In the current study, using micro(RNA) arrays, we found a ubiquitous loss of miR-126 expression in colon cancer lines when compared to normal human colon epithelia. Reconstitution of miR-126 in colon cancer cells resulted in a significant growth reduction as evidenced in clonogenic assays. A search for miR-126 gene targets revealed p85 beta, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR-126 in cancer cells induced a >= 3-fold reduction in p85 beta protein levels, with no concomitant change in p85 alpha, a gene that is functionally related to p85 beta but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85 beta-3' untranslated region is directly targeted by miR-126 Furthermore, this miR-126 mediated reduction of p85 beta was accompanied by a substantial reduction in phosphorylated AKT levels in the cancer cells, suggesting an impairment in PI3K signaling. Finally, in a panel of matched normal colon and primary colon tumors, each of the tumors demonstrated miR-126 down-regulation together with an increase in the p85 beta protein level. Taken together, we propose that mill 126 regulates PI3K signaling partly by targeting p85 beta, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis. (c) 2008 Wiley-Liss, Inc.