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

Forloni M, Dogra SK, Dong Y, Conte D, Ou J, Zhu LJ, Deng A, Mahalingam M, Green MR, Wajapeyee N - Elife (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Yale University School of Medicine, New Haven, United States.

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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Related in: MedlinePlus

shRNA-mediated downrgulation of MYC in M14 cells inhibits the expression of MYC transcriptional target genes.qRT-PCR analysis of MYC targets CCDN1 and CDC25C in M14 cells transduced with MYC shRNA expression vectors relative to cells transduced with a non-specific (NS) shRNA vector.DOI:http://dx.doi.org/10.7554/eLife.01460.011
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fig2s2: shRNA-mediated downrgulation of MYC in M14 cells inhibits the expression of MYC transcriptional target genes.qRT-PCR analysis of MYC targets CCDN1 and CDC25C in M14 cells transduced with MYC shRNA expression vectors relative to cells transduced with a non-specific (NS) shRNA vector.DOI:http://dx.doi.org/10.7554/eLife.01460.011


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

Forloni M, Dogra SK, Dong Y, Conte D, Ou J, Zhu LJ, Deng A, Mahalingam M, Green MR, Wajapeyee N - Elife (2014)

shRNA-mediated downrgulation of MYC in M14 cells inhibits the expression of MYC transcriptional target genes.qRT-PCR analysis of MYC targets CCDN1 and CDC25C in M14 cells transduced with MYC shRNA expression vectors relative to cells transduced with a non-specific (NS) shRNA vector.DOI:http://dx.doi.org/10.7554/eLife.01460.011
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927633&req=5

fig2s2: shRNA-mediated downrgulation of MYC in M14 cells inhibits the expression of MYC transcriptional target genes.qRT-PCR analysis of MYC targets CCDN1 and CDC25C in M14 cells transduced with MYC shRNA expression vectors relative to cells transduced with a non-specific (NS) shRNA vector.DOI:http://dx.doi.org/10.7554/eLife.01460.011
Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Yale University School of Medicine, New Haven, United States.

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.

Show MeSH
Related in: MedlinePlus