MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma
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https://doi.org/10.18632/oncoscience.99
Regina A. Oyesanya1,2,*, Shilpa Bhatia1,*, Mitchell E. Menezes1,*, Catherine I. Dumur3, Karan P Singh4, Sejong Bae4, Dean A. Troyer5, Robert B. Wells6, Edward R. Sauter7, David Sidransky8, Paul B. Fisher1, Oliver J. Semmes5 and Santanu Dasgupta9
1 Department of Human and Molecular Genetics, Virginia Commonwealth University, Virginia
2 Department of Biology, Norfolk State University, Virginia
3 Department of Pathology, Virginia Commonwealth University, Virginia
4 University of Alabama at Birmingham Comprehensive Cancer Center’s Biostatistics and Bioinformatics Shared Facility, University of Alabama at Birmingham, Alabama
5 The Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Virginia
6 Department of Pathology, University of Texas Health Science Center at Tyler, Texas
7 Department of Surgery, University of Texas Health Science Center at Tyler, Texas
8 Department of Otolaryngology and Head-Neck Surgery, The Johns Hopkins School of Medicine, Maryland
9 Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Texas
* These authors contributed equally to this work
Correspondence:
Santanu Dasgupta, email:
Keywords: Head and neck suqamous cell carcinoma, MDA-9/Syntenin, differentiation, SPRR1B, VEGFR1
Received: August 7, 2014 Accepted: November 16, 2014 Published: November 18, 2014
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.
