The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers.
The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers.
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DOI：
10.1002/gcc.20596
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发表时间：
2008-11
影响因子：
3.7
通讯作者：
Guda, Kishore
中科院分区：
文献类型：
--
作者：
Guo, Chunguang;Sah, Jerome F.;Beard, Lydia;Willson, James K. V.;Markowitz, Sanford D.;Guda, Kishore
MicroRNAs （miRNA/miR）是一类小的非编码rna，与各种恶性肿瘤的发病机制有关。在目前的研究中，我们使用微（RNA）阵列发现，与正常的人类结肠上皮细胞相比，结肠癌细胞系中miR-126的表达普遍缺失。结肠癌细胞中miR-126的重组导致生长显著减少，这在克隆实验中得到了证明。对miR-126基因靶点的研究发现，参与稳定和传播PI3K信号的调控亚基p85β是潜在底物之一。癌细胞中miR-126的恢复诱导p85β蛋白水平降低≥3倍，而p85α没有伴随变化，p85α是一种与p85β在功能上相关的基因，但不是miR-126的假设靶标。此外，使用报告基因构建，我们发现p85β-3 ' UTR是miR-126的直接靶向。此外，miR-126介导的p85β的减少伴随着癌细胞中磷酸化AKT水平的大幅降低，这表明PI3K信号通路受损。最后，在一组匹配的正常结肠和原发性结肠肿瘤中，每个肿瘤都表现出miR-126的下调以及p85β蛋白水平的升高。综上所述，我们提出miR-126通过靶向p85β部分调节PI3K信号，miR-126的缺失可能在结肠癌发生过程中提供选择性生长优势。
MicroRNAs (miRNA/miR) are a class of small non-coding 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 PI3K signal, as one of the potential substrates. Restoration of miR-126 in cancer cells induced a ≥3-fold reduction in p85β protein levels, with no concomitant change in p85α, 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′ UTR 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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影响因子：
29
作者：
Luo, Ji;Sobkiw, Cassandra L.;Cantley, Lewis C.
通讯作者：
Cantley, Lewis C.
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
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Enright AJ
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37.3
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Bandrés E;Cubedo E;Agirre X;Malumbres R;Zárate R;Ramirez N;Abajo A;Navarro A;Moreno I;Monzó M;García-Foncillas J
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García-Foncillas J
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64.5
作者：
van de Wetering, M;Sancho, E;Clevers, H
通讯作者：
Clevers, H
影响因子：
8
作者：
Grady, W. M.;Parkin, R. K.;Tewari, M.
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Tewari, M.