title: cRGD inhibits vasculogenic mimicry formation by down-regulating uPA expression and reducing EMT in ovarian cancer.
abstract: Vasculogenic minicry (VM), an alternative blood supply modality except to endothelial cells-mediated vascular network, is a potential therapeutic target for ovarian cancer due to VM correlated with poor prognosis in ovarian cancer patients. Accelerated extracellular matrix (ECM) degradation is prerequisite for VM formation induced by epithelial-mesenchymal transition (EMT). Previous reports demonstrate uPA has ability to degrade ECM thereby promoting tumor angiogenesis. Also, exogenous cRGD sequence enables to modulate uPA expression, attenuate EMT and suppress endothelial-lined channels. Till now, the correlation of uPA and VM formation and the effect of exogenous cRGD on VM formation remain unknown. Herein, we validate uPA expression is positively correlated with VM formation in ovarian cancer tissues (90 cases) and ovarian cancer cells (SKOV-3, OVCAR-3 and A2780 cells). In particular, silencing uPA experiments show that down-regulated uPA causes notable decrease for the complete channels formed by SKOV-3 and OVCAR-3 cells. Mechanism study discloses uPA promotes VM formation by regulating AKT/mTOR/MMP-2/Laminin5γ2 signal pathway. The result demonstrates uPA may serve as therapeutic target of VM for ovarian cancer. Also, it is found exogenous cRGD enables to inhibit VM formation in ovarian cancer via not only down-regulating uPA expression but also reducing EMT. Exogenous cRGD may be a promising angiogenic inhibitor for ovarian cancer therapy due to its inhibiting effect on VM formation as well as endothelial cells-mediated vascular network.
authors.affiliation: Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.|Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Reproductive Medicine Center, The Women and Children Hospital of Guangdong, Guangzhou Medical University, Guangzhou 511442, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wanxian
authors.initials: W
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011379:Prognosis; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: D014408:Biomarkers, Tumor; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D014568:Urokinase-Type Plasminogen Activator
keywords: cRGD; epithelial-mesenchymal transition; ovarian cancer; uPA; vasculogenic mimicry