miR-146a promotes the initiation and progression of melanoma by activating Notch signaling
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 knoc...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2014-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/01460 |
| _version_ | 1811235860764426240 |
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| author | Matteo Forloni Shaillay Kumar Dogra Yuying Dong Darryl Conte Jr Jianhong Ou Lihua Julie Zhu April Deng Meera Mahalingam Michael R Green Narendra Wajapeyee |
| author_facet | Matteo Forloni Shaillay Kumar Dogra Yuying Dong Darryl Conte Jr Jianhong Ou Lihua Julie Zhu April Deng Meera Mahalingam Michael R Green Narendra Wajapeyee |
| author_sort | Matteo Forloni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T11:59:20Z |
| format | Article |
| id | doaj.art-a6139322c3854006a2c36a922c875e1d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T11:59:20Z |
| publishDate | 2014-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a6139322c3854006a2c36a922c875e1d2022-12-22T03:33:53ZengeLife Sciences Publications LtdeLife2050-084X2014-02-01310.7554/eLife.01460miR-146a promotes the initiation and progression of melanoma by activating Notch signalingMatteo Forloni0Shaillay Kumar Dogra1Yuying Dong2Darryl Conte Jr3Jianhong Ou4Lihua Julie Zhu5April Deng6Meera Mahalingam7Michael R Green8Narendra Wajapeyee9Department of Pathology, Yale University School of Medicine, New Haven, United StatesSingapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, SingaporeDepartment of Pathology, Yale University School of Medicine, New Haven, United StatesProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, United StatesProgram in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United StatesPrograms in Gene Function and Expression, Molecular Medicine, and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United StatesDepartment of Pathology, University of Massachusetts Medical School, Worcester, United StatesDermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, United StatesProgram 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 StatesDepartment of Pathology, Yale University School of Medicine, New Haven, United StatesOncogenic 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.https://elifesciences.org/articles/01460miRNABRAFNRASmelanoma |
| spellingShingle | Matteo Forloni Shaillay Kumar Dogra Yuying Dong Darryl Conte Jr Jianhong Ou Lihua Julie Zhu April Deng Meera Mahalingam Michael R Green Narendra Wajapeyee miR-146a promotes the initiation and progression of melanoma by activating Notch signaling eLife miRNA BRAF NRAS melanoma |
| title | miR-146a promotes the initiation and progression of melanoma by activating Notch signaling |
| title_full | miR-146a promotes the initiation and progression of melanoma by activating Notch signaling |
| title_fullStr | miR-146a promotes the initiation and progression of melanoma by activating Notch signaling |
| title_full_unstemmed | miR-146a promotes the initiation and progression of melanoma by activating Notch signaling |
| title_short | miR-146a promotes the initiation and progression of melanoma by activating Notch signaling |
| title_sort | mir 146a promotes the initiation and progression of melanoma by activating notch signaling |
| topic | miRNA BRAF NRAS melanoma |
| url | https://elifesciences.org/articles/01460 |
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