title: miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Shujing
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Marilda
authors.initials: M
authors.lastname: Beqiri
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Karakousis
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
authors.forename: Weiting
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C069077:BMI1 protein, human; D007211:Indoles; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D063150:Polycomb Repressive Complex 1; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; Bmi1; epithelial-mesenchymal transition; melanoma; miR-200c