title: MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.
abstract: Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Virginia.|Department of Biology, Norfolk State University, Virginia.
authors.forename: Regina A
authors.initials: RA
authors.lastname: Oyesanya
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Virginia.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Virginia.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Virginia.
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dumur
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center's Biostatistics and Bioinformatics Shared Facility, University of Alabama at Birmingham, Alabama.
authors.forename: Karan P
authors.initials: KP
authors.lastname: Singh
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center's Biostatistics and Bioinformatics Shared Facility, University of Alabama at Birmingham, Alabama.
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.affiliation: The Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Virginia.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.affiliation: Department of Pathology, University of Texas Health Science Center at Tyler, Texas.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Wells
authors.affiliation: Department of Surgery, University of Texas Health Science Center at Tyler, Texas.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.affiliation: Department of Otolaryngology and Head-Neck Surgery, The Johns Hopkins School of Medicine, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Virginia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: The Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Virginia.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Semmes
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Texas.
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
keywords: Head and neck suqamous cell carcinoma; MDA-9/Syntenin; SPRR1B; VEGFR1; differentiation