机构：[1]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA[2]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[3]The Wistar Institute, Philadelphia, PA, USA[4]Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China中山大学附属第三医院[5]Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA[6]Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA[7]Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA[8]Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA[9]Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China[10]State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China浙江大学医学院附属第一医院
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.
基金：
CA-116103, AR-054593S1
and AR-054593 from National Institutes of Health to X.X.
第一作者机构：[1]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Liu Shujing,Tetzlaff Michael T.,Wang Tao,et al.miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment[J].PIGMENT CELL & MELANOMA RESEARCH.2015,28(4):431-41.doi:10.1111/pcmr.12379.
APA：
Liu, Shujing,Tetzlaff, Michael T.,Wang, Tao,Yang, Ruifeng,Xie, Lin...&Xu, Xiaowei.(2015).miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment.PIGMENT CELL & MELANOMA RESEARCH,28,(4)
MLA：
Liu, Shujing,et al."miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment".PIGMENT CELL & MELANOMA RESEARCH 28..4(2015):431-41
