MiR-146a Promotes the Initiation and Progression of Melanoma by Activating Notch Signaling

Overview

Journal Elife

Specialty Biology

Date 2014 Feb 20

PMID 24550252

Citations 59

Authors

Matteo Forloni

Shaillay Kumar Dogra

Yuying Dong

Darryl Conte Jr

Jianhong Ou

Lihua Julie Zhu

April Deng

Meera Mahalingam

Michael R Green

Narendra Wajapeyee

Affiliations

Soon will be listed here.

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.

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