title: VEGF/NRP-1axis promotes progression of breast cancer via enhancement of epithelial-mesenchymal transition and activation of NF-κB and β-catenin.
abstract: Autocrine vascular endothelial growth factor (VEGF) can regulate the survival and progression of cancers through its various receptors. But the mechanisms and mediators for these functions are largely uncovered, especially in breast cancer. We examined the potential roles and mechanisms of VEGF/neuropilin-1 (NRP-1) axis in regulating the tumorigenesis and metastasis of breast cancer and found the expression of VEGF and NRP-1 correlated with aggressiveness of breast cancer. Knockdown of VEGF or NRP-1 inhibited the proliferation, migration and invasion, but enhanced the apoptosis of MDA-MB-231 cells. In contrast, induction of NRP-1 over-expression promoted the proliferation, migration and invasion of MCF-7 cells. VEGF or NRP-1 silencing attenuated the epithelial-mesenchymal transition (EMT) process and the activation of NF-κBp65, but enhanced GSK-3β expression in MDA-MB-231 cells while NRP-1 over-expression reversed the effects in MCF-7 cells. Treatment with hVEGF165 did not change the inhibition in NRP-1 silencing MDA-MB-231 cells, but enhanced the aggressiveness of NRP-1 over-expressing MCF-7 cells. In addition, VEGF-silencing inhibited the growth and metastasis of implanted MDA-MB-231 tumors in vivo. Our novel data suggest that the positive regulation of the VEGF/NRP-1 axis on the tumorigenesis and metastasis of breast cancer may be associated with enhancing the EMT process and the NF-κB and β-catenin signaling. Hence, the VEGF/NRP-1 axis may be a valuable target for design of therapies for intervention of breast cancer.
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Minna
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province 710068, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Radiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province 710068, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Shao
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Shangke
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Radiotherapy, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Du
authors.initials: D
authors.lastname: Meng
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China. Electronic address: qintj70@126.com.
authors.forename: Tianjie
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China. Electronic address: zhaoxinhanprof@163.com.
authors.forename: Xinhan
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D016328:NF-kappa B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D039942:Neuropilin-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Breast cancer; Epithelial-mesenchymal transition; NRP-1; Tumor progression; VEGF