TY - JOUR
T1 - miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment
AU - Liu, Shujing
AU - Tetzlaff, Michael T.
AU - Wang, Tao
AU - Yang, Ruifeng
AU - Xie, Lin
AU - Zhang, Gao
AU - Krepler, Clemens
AU - Xiao, Min
AU - Beqiri, Marilda
AU - Xu, Wei
AU - Karakousis, Giorgos
AU - Schuchter, Lynn
AU - Amaravadi, Ravi K.
AU - Xu, Weiting
AU - Wei, Zhi
AU - Herlyn, Meenhard
AU - Yao, Yuan
AU - Zhang, Litao
AU - Wang, Yingjie
AU - Zhang, Lin
AU - Xu, Xiaowei
N1 - Publisher Copyright:
© 2015 John Wiley & Sons A/S.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
KW - BRAF inhibitor
KW - Bmi1
KW - Epithelial-mesenchymal transition
KW - Melanoma
KW - MiR-200c
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U2 - 10.1111/pcmr.12379
DO - 10.1111/pcmr.12379
M3 - Article
C2 - 25903073
AN - SCOPUS:84930923522
SN - 1755-1471
VL - 28
SP - 431
EP - 441
JO - Pigment Cell and Melanoma Research
JF - Pigment Cell and Melanoma Research
IS - 4
ER -