miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment

Shujing Liu, Michael T. Tetzlaff, Tao Wang, Ruifeng Yang, Lin Xie, Gao Zhang, Clemens Krepler, Min Xiao, Marilda Beqiri, Wei Xu, Giorgos Karakousis, Lynn Schuchter, Ravi K. Amaravadi, Weiting Xu, Zhi Wei, Meenhard Herlyn, Yuan Yao, Litao Zhang, Yingjie Wang, Lin ZhangXiaowei Xu

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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 microRNAs 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.

Original languageEnglish (US)
Pages (from-to)431-441
Number of pages11
JournalPigment Cell and Melanoma Research
Volume28
Issue number4
DOIs
StatePublished - Jul 1 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Oncology
  • Dermatology

Keywords

  • BRAF inhibitor
  • Bmi1
  • Epithelial-mesenchymal transition
  • Melanoma
  • MiR-200c

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