title: Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling.
abstract: OBJECTIVE
  Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression.
  
  
  METHODS
  Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors.
  
  
  RESULTS
  Significantly higher (P=0.002-0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage (P=0.01), grade (P=0.03), and invasion status (P=0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation (P=0.0012), invasion (P=0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (P=0.04, EGFR; P=0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage (P=0.03) and invasion (P=0.04) was also evident.
  
  
  CONCLUSIONS
  Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA. sdasgupta@vcu.edu
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Janjic
authors.forename: Shilpa
authors.initials: S
authors.lastname: Bhatia
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology*
chemical_list: C109621:SDCBP protein, human; D053676:Syntenins; C512478:EGFR protein, human; D066246:ErbB Receptors