Abstract
Angiogenesis is crucial for the progression of esophageal squamous cell carcinoma (ESCC). Anti‑angiogenesis 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 IQ‑domain GTPase activating protein1 (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 invitro and invivo. 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 invitro and chicken embryo chorioallantoic membrane (CAM) assay invivo. Moreover, IQGAP1 overexpression in ESCC cells increased expression of vascular endothelial growth factor (VEGF) and phosphorylation of vascular endothelial growth factor receptor2 (VEGFR2). Meanwhile, we found that levels of AKT and ERK phosphorylation were upregulated in IQGAP1‑overexpressing cells. Importantly, IQGAP1‑knockdown cells showed the opposing results. Furthermore, AKT and ERK inhibitors not only significantly decreased VEGF expression and VEGFR2 phosphorylation in IQGAP1‑overexpressing cells, but also abolished the pro‑angiogenic 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 ERK‑mediated VEGF‑VEGFR2 signaling pathway in ESCC, and IQGAP1 may be an attractive therapeutic target for cancer anti‑angiogenesis treatment.
Highlights
Esophageal cancer is one of the most aggressive and fatal gastrointestinal tract malignancies worldwide
We reported that IQ‐domain GTPase activating protein 1 (IQGAP1) is highly overexpressed in Esophageal squamous cell carcinoma (ESCC) and the knockdown of IQGAP1 by small interfering RNA can decrease cell proliferation and metastasis ability in vitro and in vivo [14], indicating that IQGAP1 is a potential target for cancer treatment
We report that IQGAP1 overexpression promotes angiogenesis of ESCC by the AKT and ERK‐mediated vascular endothelial growth factor (VEGF)‐vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway
Summary
Esophageal cancer is one of the most aggressive and fatal gastrointestinal tract malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal cancer in China [1]. The underlying mechanisms involved in the initiation and progression of ESCC are not fully understood. A thorough understanding of the molecular mechanisms underlying the carcinogenesis and progression of ESCC is vital for discovering novel targets and innovative treatment strategies. Angiogenesis, the process leading to the formation of new blood vessels from preexisting ones, is one of the major hallmarks of cancer, and is involved in the progression and growth of cancer [2,3]. Understanding the molecular mechanisms responsible for tumor angiogenesis can benefit cancer diagnosis and treatment. Suppression of tumor angiogenesis offers a promising strategy for targeted therapy of cancer
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