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MiR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

ABSTRACT: Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001.

SUBMITTER: Forloni M

PROVIDER: S-EPMC3927633 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

Forloni Matteo M Dogra Shaillay Kumar SK Dong Yuying Y Conte Darryl D Ou Jianhong J Zhu Lihua Julie LJ Deng April A Mahalingam Meera M Green Michael R MR Wajapeyee Narendra N

eLife 20140218

Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146 ...[more]

PMID: 24550252

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Project description:Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1? was identified as the transcription mediator of miR-1275. Activation of Wnt/?-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/?-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/?-catenin and Notch pathways, including DKK3, SFRP1, GSK3?, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/?-catenin and Notch signaling pathways. Thus, HIF-1?-regulated miR-1275 might be a potential therapeutic target for LUAD.

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MiR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

Publications

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

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