Monocyte chemoattractant protein-1(MCP-1)is a chemotactic cytokine that can bind to its receptor cysteine-cysteine chemokine receptor 2(CCR2)and plays an important role in breast cancer cell metastasis.However,the mol...Monocyte chemoattractant protein-1(MCP-1)is a chemotactic cytokine that can bind to its receptor cysteine-cysteine chemokine receptor 2(CCR2)and plays an important role in breast cancer cell metastasis.However,the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood.Here,we showed that MCP-1 stimulated the epithelial-mesenchymal transition(EMT)and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin,upregulating vimentin and fibronectin,activating matrix metallopeptidase-2(MMP-2),and promoting migration and invasion.Moreover,MCP-1 treatment reduced glycogen synthase kinase-3β(GSK-3β)activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells.The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3βand decreased the expression of Snail,an EMT-related transcription factor,leading to the inhibition of MCF-7 cell migration and invasion.Inactivation of GSK-3βby LiCl(lithium chloride)treatment notably increased MMP-2 activity,vascular endothelial growth factor expression and EMT of MCF-7 cells.These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway,and identified a potential novel target for therapeutic intervention in breast cancer.展开更多
基金supported,in part or in its entirety,by grants from the National Natural Science Foundation of China(11272083,31470906,11502049,81471785 and 31470959)the Sichuan Youth Science and Technology Foundation of China(2014JQ0008).
文摘Monocyte chemoattractant protein-1(MCP-1)is a chemotactic cytokine that can bind to its receptor cysteine-cysteine chemokine receptor 2(CCR2)and plays an important role in breast cancer cell metastasis.However,the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood.Here,we showed that MCP-1 stimulated the epithelial-mesenchymal transition(EMT)and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin,upregulating vimentin and fibronectin,activating matrix metallopeptidase-2(MMP-2),and promoting migration and invasion.Moreover,MCP-1 treatment reduced glycogen synthase kinase-3β(GSK-3β)activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells.The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3βand decreased the expression of Snail,an EMT-related transcription factor,leading to the inhibition of MCF-7 cell migration and invasion.Inactivation of GSK-3βby LiCl(lithium chloride)treatment notably increased MMP-2 activity,vascular endothelial growth factor expression and EMT of MCF-7 cells.These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway,and identified a potential novel target for therapeutic intervention in breast cancer.
