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miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment.
- Source :
-
Pigment Cell & Melanoma Research . Jul2015, Vol. 28 Issue 4, p431-441. 12p. - Publication Year :
- 2015
-
Abstract
- Resistance to BRAF inhibitors ( BRAFi) is one of the major challenges for targeted therapies for BRAF-mutant melanomas. However, little is known about the role of micro RNAs in conferring BRAFi resistance. Herein, we demonstrate that miR-200c expression is significantly reduced whereas miR-200c target genes including Bmi1, Zeb2, Tubb3, ABCG5, and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pretreatment tumor biopsies. Similar changes were observed in BRAFi-resistant melanoma cell lines. Overexpression of miR-200c or knock-down of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/ AKT and MAPK signaling cascades, and acquisition of epithelial-mesenchymal transition-like phenotypes, including upregulation of E-cadherin, downregulation of N-cadherin, and ABCG5 and MDR1 expression. Conversely, knock-down of miR-200c or overexpression of Bmi1 in BRAFi-sensitive melanoma cells activates the PI3K/ AKT and MAPK pathways, upregulates N-cadherin, ABCG5, and MDR1 expression, and downregulates E-cadherin expression, leading to BRAFi resistance. Together, our data identify miR-200c as a critical signaling node in BRAFi-resistant melanomas impacting the MAPK and PI3K/ AKT pathways, suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 17551471
- Volume :
- 28
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Pigment Cell & Melanoma Research
- Publication Type :
- Academic Journal
- Accession number :
- 103223987
- Full Text :
- https://doi.org/10.1111/pcmr.12379