Overexpression of IQGAP1 promotes the angiogenesis of esophageal squamous cell carcinoma through the AKT and ERK­mediated VEGF­VEGFR2 signaling pathway.

Angiogenesis is crucial for the progression of esophageal squamous cell carcinoma (ESCC). Anti­angiogenesis by targeting important molecules has been considered as one of the most promising and efficient strategy for cancer therapy. Recent studies have demonstrated that the IQ­domain GTPase activating protein 1 (IQGAP1) plays critical roles in tumorigenesis and cancer progression. We previously reported that IQGAP1 is overexpressed in ESCC, and IQGAP1 knockdown can decrease cell proliferation and metastasis ability in vitro and in vivo. However, the effects of IQGAP1 on the angiogenesis of ESCC and its underlying mechanisms remain unknown. In the present study, we found that IQGAP1 overexpression promoted tumor angiogenesis confirmed by human umbilical vascular endothelial cell (HUVEC) tube formation in vitro and chicken embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, IQGAP1 overexpression in ESCC cells increased expression of vascular endothelial growth factor (VEGF) and phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). Meanwhile, we found that levels of AKT and ERK phosphorylation were upregulated in IQGAP1­overexpressing cells. Importantly, IQGAP1­knockdown cells showed the opposing results. Furthermore, AKT and ERK inhibitors not only significantly decreased VEGF expression and VEGFR2 phosphorylation in IQGAP1­overexpressing cells, but also abolished the pro­angiogenic effect of IQGAP1 overexpression on angiogenesis in the HUVEC tube formation and chicken embryo CAM assay. Taken together, this evidence confirms that IQGAP1 overexpression promotes tumor angiogenesis via the AKT and ERK­mediated VEGF­VEGFR2 signaling pathway in ESCC, and IQGAP1 may be an attractive therapeutic target for cancer anti­angiogenesis treatment.