Loss of breast cancer metastasis suppressor 1 promotes ovarian cancer             cell metastasis by increasing chemokine receptor 4 expression.
Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. It has been demonstrated that BRMS1 may be correlated with advanced ovarian cancer. The aim of this study was to investi-gate the mechanisms of BRMS1 involvement in ovarian cancer metastasis. We constructed a plasmid containing a short hairpin RNA (shRNA) against BRMS1 and transfected it into the ovarian cancer cell line OVCAR3. Real-time reverse transcription polymerase chain reaction (real-time PCR) and Western blot analyses demonstrated that BRMS1 expression was efficiently downregulated. Stable suppression of BRMS1 significantly enhanced cell adhesion, migration, invasion and angiogenesis. We also found that chemokine receptor 4 (CXCR4) was upregulated at both the mRNA and protein levels. When approaching for the mechanism, we discovered that activation of the nuclear factor-κB (NF-κB) signaling pathway mediated CXCR4 upregulation, as demonstrated by the electrophoretic mobility shift assay (EMSA). Collectively, these results suggest that attenuation of BRMS1 may play a critical role in promoting migration, invasion and angiogenesis of ovarian cancer cells and BRMS1 may regulate the metastatic potential at least in part through upregulation of CXCR4 via NF-κB activation. Restoration of BRMS1 function is thus a potential new strategy for treating human ovarian cancer.
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou 510150, PR China. xjsheng@gzemail.cn
Xiu-Jie
XJ
Sheng
Ying-Qun
YQ
Zhou
Qing-Yuan
QY
Song
Dong-Mei
DM
Zhou
Qi-Cai
QC
Liu
D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000378:metabolism; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015316:Genetic Therapy; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
C410024:BRMS1 protein, human; C527276:CXCR4 protein, human; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D012097:Repressor Proteins