Overexpression of IQGAP1 promotes the angiogenesis of esophageal squamous cell carcinoma through the AKT and ERK‑mediated VEGF‑VEGFR2 signaling pathway

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 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 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.

CCL3–CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways

“…MMP-2 and MMP-9 remodel extracellular matrix and contribute to cell invasion, and VEGF-A promotes angiogenesis in various malignancies [ 6 ]. In ESCC, MMP-2 and MMP-9 contribute to tumor invasion and metastasis [ 58 , 59 ], and VEGFs including VEGF-A contribute to angiogenesis and are associated with high microvascular density and poor patient prognosis [ 60 – 62 ]. MMP-2 is involved in CCL3-dependent cell invasion in oral squamous cell carcinoma [ 27 ] and chondrosarcoma [ 21 ], whereas MMP-9 is involved in CCL3-dependent cell invasion in hepatocellular carcinoma [ 17 ] and oral squamous cell carcinoma [ 27 ].…”

“…VEGF-A is involved in CCL3-dependent angiogenesis in osteosarcoma [ 23 ] and is also upregulated downstream of the CCL3–CCR5 axis in oral squamous cell carcinoma [ 27 ]. Activating the PI3K/Akt and MEK/ERK pathways induces the expressions of MMP-2, MMP-9, and VEGF-A in various malignancies including ESCC [ 62 – 65 ]. Our present results demonstrated that treatment with rhCCL3 upregulated the MMP2 mRNA expression in three ESCC cell lines universally, and the VEGFA mRNA expression in two ESCC cell lines.…”

<p>Integrative Analysis of the IQ Motif-Containing GTPase-Activating Protein Family Indicates That the IQGAP3-PIK3C2B Axis Promotes Invasion in Colon Cancer</p>

“…IQGAP1 is reported to be upregulated in many human cancers and associated with enhanced malignant behaviours. [42][43][44] In contrast, the characteristics of IQGAP3 are less studied, though it may have a role similar that of to IQGAP1 in tumorigenesis. In our study, we compared IQGAP3 expression in 40 paired CRC tissues, which provided important evidence showing IQGAP3 to be upregulated in CRC tissue.…”

<p>Parthenolide Inhibits Angiogenesis in Esophageal Squamous Cell Carcinoma Through Suppression of VEGF</p>

“…6 The growth and progression of solid tumors, including esophageal cancer, depend on tumor angiogenesis. 7 Anti-angiogenesis therapy has also been proven to be an effective strategy for the treatment of solid tumors. VEGF is the main angiogenesis promoting factor; therefore, anti-VEGF treatment is an effective anti-angiogenesis treatment strategy of tumors.…”