miR-146a promotes the initiation and progression of melanoma by activating Notch signaling
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
Matteo Forloni
Department of Pathology, Yale University School of Medicine, New Haven, United States
Shaillay Kumar Dogra
Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
Yuying Dong
Department of Pathology, Yale University School of Medicine, New Haven, United States
Darryl Conte Jr
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Jianhong Ou
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United States
Lihua Julie Zhu
Programs in Gene Function and Expression, Molecular Medicine, and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States
April Deng
Department of Pathology, University of Massachusetts Medical School, Worcester, United States
Meera Mahalingam
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, United States
Michael R Green
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Program in Gene Function and Expression, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
Narendra Wajapeyee
Department of Pathology, Yale University School of Medicine, New Haven, United States
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.
