Overexpression of Antiangiogenic Vascular Endothelial Growth Factor Isoform and Splicing Regulatory Factors in Oral, Laryngeal and Pharyngeal Squamous Cell Carcinomas

BACKGROUND: Overexpression of proangiogenic vascular endothelial growth factor A family VEGFA(xxx) is associated with tumor growth and metastasis. The role of the alternatively spliced antiangiogenic family VEGFA(xxx)b is poorly investigated in head and neck squamous cell carcinomas (HNSCCs). The antiangiogenic isoform binds to bevacizumab and its expression level could influence the treatment response and progression-free survival. In this study, the relative expression of VEGFA(xxx) and VEGFA(165)b isoforms and splicing regulatory factors genes was investigated in a series of HNSCCs. METHODS: VEGFA(xxx), VEGFA(165)b, SRSF6, SRSF5, SRSF1 and SRPK1 gene expression was quantified by quantitative real time PCR in 53 tissue samples obtained by surgery from HNSCC patients. Protein expression was evaluated by immunohistochemistry. RESULTS: VEGFA(xxx) and VEGFA(165)b were overexpressed in HNSCCs. Elevated protein expression was also confirmed. However, VEGFA isoforms demonstrated differential expression according to anatomical sites. VEGFA(xxx) was overexpressed in pharyngeal tumors while the VEGFA(165)b isoform was up-regulated in oral tumors. The VEGFA(165)b isoform was also positively correlated with expression of the splicing regulatory genes SRSF1, SRSF6 and SRSF5. CONCLUSIONS: We concluded that VEGFA(xxx) and VEGFA(165)b isoforms are overexpressed in HNSCCs and the splicing regulatory factors SRSF1, SRSF6, SRSF5 and SRPK1 may contribute to alternative splicing of the VEGFA gene. The findings for the differential expression of the antiangiogenic isoform in HNSCCs could facilitate effective therapeutic strategies for the management of these tumors.