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Loss of BMI‐1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD‐2/MyD88‐mediated NF‐κB signaling
Author(s) -
Ye Kai,
Chen QiWei,
Sun YaFeng,
Lin JianAn,
Xu JianHua
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26353
Subject(s) - cancer research , tumor microenvironment , epithelial–mesenchymal transition , gene knockdown , vimentin , inflammation , tlr4 , downregulation and upregulation , chemistry , metastasis , cancer , biology , medicine , immunology , apoptosis , immunohistochemistry , biochemistry , gene , tumor cells
Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment created by immune cells facilitates tumor migration. Epithelial‐mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in an inflammatory microenvironment. B‐lymphoma Moloney murine leukemia virus insertion region 1 (BMI‐1) acts as an oncogene in various tumors. Ectopic expression of Bmi‐1 have an effect on EMT and invasiveness. The purpose of this study was to investigate the efficacy of BMI‐1 on inflammation‐induced tumor migration and EMT and the underlying mechanism. We observed that the expression of BMI‐1, TNF‐α, and IL‐1β was significantly increased in HT29 and HCT116 cells after THP‐1 Conditioned‐Medium (THP‐1‐CM) stimulation. Additionally, inhibition of BMI‐1 impeded cell invasion induced by THP‐1‐CM‐stimulation in both HT29 and HCT116 cells. BMI‐1 knockdown remarkably repressed THP‐1‐CM—induced EMT by regulating the expression of EMT biomarkers with an increase in E‐cadherin accompanied by decrease in N‐cadherin and vimentin. Furthermore, downregulation of BMI‐1 dramatically impeded THP‐1‐CM‐triggered Toll‐like receptor 4(TLR4)/myeloid differentiation protein 2(MD‐2)/myeloid differentiation factor 88(MyD88) activity by repressing the expression of the TLR4/MD‐2 complex and MyD88. Further data demonstrated that knockout of BMI‐1 also dampened NF‐κB THP‐1‐CM‐triggered activity. Taken all data together, our findings established that BMI‐1 modulated TLR4/MD‐2/MyD88 complex‐mediated NF‐κB signaling involved in inflammation‐induced cancer cells invasion and EMT, and therefore, could be a potential chemopreventive agent against inflammation‐associated colorectal cancer. Highlights. Establishment of an inflammatory microenvironment. Suppression of BMI‐1 reverses THP‐1‐CM‐induced inflammatory cytokine production in CRC. Loss of BMI‐1 suppressed TLR4/MD‐2/MyD88 complex‐mediated NF‐κB signaling.