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
Liver is the most common metastatic site for colorectal cancer(CRC),there is no satisfied approach to treat CRC liver metastasis(CRCLM).Here,we investigated the role of a polycomb protein BMI-1 in CRCLM.Immunohistoche...Liver is the most common metastatic site for colorectal cancer(CRC),there is no satisfied approach to treat CRC liver metastasis(CRCLM).Here,we investigated the role of a polycomb protein BMI-1 in CRCLM.Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage,invasion depth and right-sided primary tumor.Knockdown BMI-1 in high metastatic HCT116 and LOVO cells repressed the migratory/invasive phenotype and reversed epithelialemesenchymal transition(EMT),while BMI-1 overexpression in low metastatic Ls174 T and DLD1 cells enhanced invasiveness and EMT.The effects of BMI-1 in CRC cells were related to upregulating snail via AKT/GSK-3βpathway.Furthermore,knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model.Meanwhile,BMI-1 overexpression in Ls174 T and DLD1 significantly increased CRCLM.Moreover,sodium butyrate,a histone deacetylase and BMI-1 inhibitor,reduced HCT116 and LOVO liver metastasis in immunodeficient mice.Our results suggest that BMI-1 is a major regulator of CRCLM and provide a potent molecular target for CRCLM treatment.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.
基金supported by the National Natural Science Foundation of China(Nos.81272493 and 81472213)the Health Commission of Zhejiang Province(Nos.2019331258 and 2019335600,China)+1 种基金Natural Sciences Foundation of Zhejiang Province(No.LY17H220001,China)the Science Technology Department of Zhejiang Province(Nos.LGF20H220001 and 2015C37112,China)。
文摘Liver is the most common metastatic site for colorectal cancer(CRC),there is no satisfied approach to treat CRC liver metastasis(CRCLM).Here,we investigated the role of a polycomb protein BMI-1 in CRCLM.Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage,invasion depth and right-sided primary tumor.Knockdown BMI-1 in high metastatic HCT116 and LOVO cells repressed the migratory/invasive phenotype and reversed epithelialemesenchymal transition(EMT),while BMI-1 overexpression in low metastatic Ls174 T and DLD1 cells enhanced invasiveness and EMT.The effects of BMI-1 in CRC cells were related to upregulating snail via AKT/GSK-3βpathway.Furthermore,knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model.Meanwhile,BMI-1 overexpression in Ls174 T and DLD1 significantly increased CRCLM.Moreover,sodium butyrate,a histone deacetylase and BMI-1 inhibitor,reduced HCT116 and LOVO liver metastasis in immunodeficient mice.Our results suggest that BMI-1 is a major regulator of CRCLM and provide a potent molecular target for CRCLM treatment.
