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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

Ectopic expression of MEK DD stimulates the transcription of MAP kinase target genes.qRT-PCR analysis of MEK-ERK transcriptional targets FOS, EGR1 and FOSL1 in MEL-ST cells expressing either a empty vector or constitutively active MEK (MEK DD).DOI:http://dx.doi.org/10.7554/eLife.01460.008
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fig1s5: Ectopic expression of MEK DD stimulates the transcription of MAP kinase target genes.qRT-PCR analysis of MEK-ERK transcriptional targets FOS, EGR1 and FOSL1 in MEL-ST cells expressing either a empty vector or constitutively active MEK (MEK DD).DOI:http://dx.doi.org/10.7554/eLife.01460.008

Mentions: To further confirm that increased BRAF-MEK-ERK signaling is sufficient to induce miR-146a expression, we stably expressed a constitutively active MEK derivative (MEK DD) in MEL-ST cells. Figure 1F shows that expression of MEK DD substantially increased BRAF-MEK-ERK signaling and stimulated miR-146a expression. As expected, transcriptional targets of the MAP kinase pathway were also upregulated in cells expressing MEK DD (Figure 1—figure supplement 5).


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)

Ectopic expression of MEK DD stimulates the transcription of MAP kinase target genes.qRT-PCR analysis of MEK-ERK transcriptional targets FOS, EGR1 and FOSL1 in MEL-ST cells expressing either a empty vector or constitutively active MEK (MEK DD).DOI:http://dx.doi.org/10.7554/eLife.01460.008
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1s5: Ectopic expression of MEK DD stimulates the transcription of MAP kinase target genes.qRT-PCR analysis of MEK-ERK transcriptional targets FOS, EGR1 and FOSL1 in MEL-ST cells expressing either a empty vector or constitutively active MEK (MEK DD).DOI:http://dx.doi.org/10.7554/eLife.01460.008
Mentions: To further confirm that increased BRAF-MEK-ERK signaling is sufficient to induce miR-146a expression, we stably expressed a constitutively active MEK derivative (MEK DD) in MEL-ST cells. Figure 1F shows that expression of MEK DD substantially increased BRAF-MEK-ERK signaling and stimulated miR-146a expression. As expected, transcriptional targets of the MAP kinase pathway were also upregulated in cells expressing MEK DD (Figure 1—figure supplement 5).

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