Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer.
Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer.
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可重复的组合调控网络阐明了非小细胞肺癌中新型致癌 microRNA。
DOI：
10.1261/rna.042754.113
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Mitra R;Edmonds MD;Sun J;Zhao M;Yu H;Eischen CM;Zhao Z
This study investigates the network of miRNAs, transcription factors, and their common predicted target genes in non-small cell lung cancer (NSCLC), revealing eight hub miRNAs, a novel co-regulatory module acting on the TGF-pathway centered around miR-9-5p, miR-130b-3p, and TGFBR2. While previous studies reported aberrant expression of microRNAs (miRNAs) in non-small cell lung cancer (NSCLC), little is known about which miRNAs play central roles in NSCLC's pathogenesis and its regulatory mechanisms. To address this issue, we presented a robust computational framework that integrated matched miRNA and mRNA expression profiles in NSCLC using feed-forward loops. The network consists of miRNAs, transcription factors (TFs), and their common predicted target genes. To discern the biological meaning of their associations, we introduced the direction of regulation. A network edge validation strategy using three independent NSCLC expression profiling data sets pinpointed reproducible biological regulations. Reproducible regulation, which may reflect the true molecular interaction, has not been applied to miRNA–TF co-regulatory network analyses in cancer or other diseases yet. We revealed eight hub miRNAs that connected to a higher proportion of targets validated by independent data sets. Network analyses showed that these miRNAs might have strong oncogenic characteristics. Furthermore, we identified a novel miRNA–TF co-regulatory module that potentially suppresses the tumor suppressor activity of the TGF-β pathway by targeting a core pathway molecule (TGFBR2). Follow-up experiments showed two miRNAs (miR-9-5p and miR-130b-3p) in this module had increased expression while their target gene TGFBR2 had decreased expression in a cohort of human NSCLC. Moreover, we demonstrated these two miRNAs directly bind to the 3′ untranslated region of TGFBR2. This study enhanced our understanding of miRNA–TF co-regulatory mechanisms in NSCLC. The combined bioinformatics and validation approach we described can be applied to study other types of diseases.
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影响因子：
4.3
作者：
Langfelder P;Luo R;Oldham MC;Horvath S
通讯作者：
Horvath S
影响因子：
3.7
作者：
Biswas, Swati;Trobridge, Patricia;Grady, William M.
通讯作者：
Grady, William M.
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1097/jto.0b013e3181ce3afd
发表时间：
2010-04
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Jeon HS;Jen J
通讯作者：
Jen J
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y