TY - JOUR
T1 - The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers
AU - Guo, Chunguang
AU - Sah, Jerome F.
AU - Beard, Lydia
AU - Willson, James K V
AU - Markowitz, Sanford D.
AU - Guda, Kishore
PY - 2008/11
Y1 - 2008/11
N2 - 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 p85β, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR126 in cancer cells induced a ≥3-fold reduction in p85ß protein levels, with no concomitant change in p85αa, a gene that is functionally related to p85β but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85β-3′ untranslated region is directly targeted by miR-126. Furthermore, this miR-126 mediated reduction of p85β 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 p85β protein level. Taken together, we propose that miR-126 regulates PI3K signaling partly by targeting p85β, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis.
AB - 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 p85β, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR126 in cancer cells induced a ≥3-fold reduction in p85ß protein levels, with no concomitant change in p85αa, a gene that is functionally related to p85β but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85β-3′ untranslated region is directly targeted by miR-126. Furthermore, this miR-126 mediated reduction of p85β 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 p85β protein level. Taken together, we propose that miR-126 regulates PI3K signaling partly by targeting p85β, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis.
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U2 - 10.1002/gcc.20596
DO - 10.1002/gcc.20596
M3 - Article
C2 - 18663744
AN - SCOPUS:52249096359
SN - 1045-2257
VL - 47
SP - 939
EP - 946
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
IS - 11
ER -