title: Vascular endothelial growth factor C promotes cervical cancer metastasis via up-regulation and activation of RhoA/ROCK-2/moesin cascade.
abstract: BACKGROUND
  The elevated expression of vascular endothelial growth factor C (VEGF-C) is correlated with clinical cervical cancer metastasis and patient survival, which is interpreted by VEGF-C functions to stimulate angiogenesis and lymphatic genesis. However, the direct impact of VEGF-C on cervical cancer cell motility remains largely unknown.
  
  
  METHODS
  In this study, we investigated the effects of VEGF-C on actin cytoskeleton remodeling and on cervical cancer cell migration and invasion and how the actin-regulatory protein, moesin regulated these effects through RhoA/ROCK-2 signaling pathway.
  
  
  RESULTS
  On cervical carcinoma cell line SiHa cells, exposure of VEGF-C triggered remodeling of the actin cytoskeleton and the formation of membrane ruffles, which was required for cell movement. VEGF-C significantly enhanced SiHa cells horizontal migration and three-dimensional invasion into matrices. These actions were dependent on increased expression and phosphorylation of the actin-regulatory protein moesin and specific moesin siRNA severely impaired VEGF-C stimulated-cell migration. The extracellular small GTPase RhoA/ROCK-2 cascade mediated the increased moesin expression and phosphorylation, which was discovered by the use of Y-27632, a specific inhibitor of Rho kinase and by transfected constitutively active, dominant-negative RhoA as well as ROCK-2 SiRNA. Furthermore, in the surgical cervical specimen from the patients with FIGO stage at cervical intra-epithelial neoplasia and I-II cervical squamous cell carcinoma, the expression levels of moesin were found to be significantly correlated with tumor malignancy and metastasis.
  
  
  CONCLUSIONS
  These results implied that VEGF-C promoted cervical cancer metastasis by upregulation and activation of moesin protein through RhoA/ROCK-2 pathway. Our findings offer new insight into the role of VEGF-C on cervical cancer progression and may provide potential targets for cervical cancer therapy.
authors.affiliation: Department of Gynecology and obstetrics, the first affiliated hospital of Sun Yat-sen University, Guangdong, Guangzhou, 510089, China. gz87335487@163.nt
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Qiongshan
authors.initials: Q
authors.lastname: Liu
authors.forename: Junxiu
authors.initials: J
authors.lastname: Liu
authors.forename: Jinghe
authors.initials: J
authors.lastname: Huang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fu
mesh_terms: D000199:Actins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000235:genetics / Q000556:secondary
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C066737:RHOA protein, human; C071058:moesin; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein