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

Li,Chao‑Hui; Sun,Xue‑Jiao; Niu,Shi‑Shi; Yang,Cheng‑Yuan; Hao,Yue‑Peng; Kou,Jun‑Ting; Li,Xiao‑Zhong; Wang,Xiao‑Xia

doi:10.3892/or.2018.6558

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

Authors:
- Chao‑Hui Li
- Xue‑Jiao Sun
- Shi‑Shi Niu
- Cheng‑Yuan Yang
- Yue‑Peng Hao
- Jun‑Ting Kou
- Xiao‑Zhong Li
- Xiao‑Xia Wang
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Affiliations: Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Emergency, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
Published online on: July 11, 2018 https://doi.org/10.3892/or.2018.6558
Pages: 1795-1802

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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.

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1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Carmeliet P: Angiogenesis in life, disease and medicine. Nature. 438:932–936. 2005. View Article : Google Scholar : PubMed/NCBI
3	Folkman J: Angiogenesis. Annu Rev Med. 57:1–18. 2006. View Article : Google Scholar : PubMed/NCBI
4	Johnson M, Sharma M and Henderson BR: IQGAP1 regulation and roles in cancer. Cell Signal. 21:1471–1478. 2009. View Article : Google Scholar : PubMed/NCBI
5	Noritake J, Watanabe T, Sato K, Wang S and Kaibuchi K: IQGAP1: A key regulator of adhesion and migration. J Cell Sci. 118:2085–2092. 2005. View Article : Google Scholar : PubMed/NCBI
6	White CD, Erdemir HH and Sacks DB: IQGAP1 and its binding proteins control diverse biological functions. Cell Signal. 24:826–834. 2012. View Article : Google Scholar : PubMed/NCBI
7	Nabeshima K, Shimao Y, Inoue T and Koono M: Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: Its overexpression in carcinomas and association with invasion fronts. Cancer Lett. 176:101–109. 2002. View Article : Google Scholar : PubMed/NCBI
8	Hayashi H, Nabeshima K, Aoki M, Hamasaki M, Enatsu S, Yamauchi Y, Yamashita Y and Iwasaki H: Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion. Int J Cancer. 126:2563–2574. 2010.PubMed/NCBI
9	Jadeski L, Mataraza JM, Jeong HW, Li Z and Sacks DB: IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem. 283:1008–1017. 2008. View Article : Google Scholar : PubMed/NCBI
10	Dong P, Nabeshima K, Nishimura N, Kawakami T, Hachisuga T, Kawarabayashi T and Iwasaki H: Overexpression and diffuse expression pattern of IQGAP1 at invasion fronts are independent prognostic parameters in ovarian carcinomas. Cancer Lett. 243:120–127. 2006. View Article : Google Scholar : PubMed/NCBI
11	Zhao H, Xie C, Lin X, Zhao Y, Han Y, Fan C, Zhang X, Du J, Han Y, Han Q, et al: Coexpression of IQ-domain GTPase-activating protein 1 (IQGAP1) and Dishevelled (Dvl) is correlated with poor prognosis in non-small cell lung cancer. PLoS One. 9:e1137132014. View Article : Google Scholar : PubMed/NCBI
12	Wang XX, Li XZ, Zhai LQ, Liu ZR, Chen XJ and Pei Y: Overexpression of IQGAP1 in human pancreatic cancer. Hepatobiliary Pancreat Dis Int. 12:540–545. 2013. View Article : Google Scholar : PubMed/NCBI
13	Liu Z, Liu D, Bojdani E, El-Naggar AK, Vasko V and Xing M: IQGAP1 plays an important role in the invasiveness of thyroid cancer. Clin Cancer Res. 16:6009–6018. 2010. View Article : Google Scholar : PubMed/NCBI
14	Wang XX, Wang K, Li XZ, Zhai LQ, Qu CX, Zhao Y, Liu ZR, Wang HZ, An QJ, Jing LW, et al: Targeted knockdown of IQGAP1 inhibits the progression of esophageal squamous cell carcinoma in vitro and in vivo. PLoS One. 9:e965012014. View Article : Google Scholar : PubMed/NCBI
15	Arnaoutova I, George J, Kleinman HK and Benton G: The endothelial cell tube formation assay on basement membrane turns 20: State of the science and the art. Angiogenesis. 12:267–274. 2009. View Article : Google Scholar : PubMed/NCBI
16	Ponce ML: Tube formation: An in vitro matrigel angiogenesis assay. Methods Mol Biol. 467:183–188. 2009. View Article : Google Scholar : PubMed/NCBI
17	Ribatti D, Vacca A, Roncali L and Dammacco F: The chick embryo chorioallantoic membrane as a model for in vivo research on angiogenesis. Int J Dev Biol. 40:1189–1197. 1996.PubMed/NCBI
18	Verheul HM and Pinedo HM: The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. Clin Breast Cancer. 1 Suppl 1:S80–S84. 2000. View Article : Google Scholar : PubMed/NCBI
19	Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med. 49:407–424. 1998. View Article : Google Scholar : PubMed/NCBI
20	Osman M: An emerging role for IQGAP1 in regulating protein traffic. ScientificWorldJournal. 10:944–953. 2010. View Article : Google Scholar : PubMed/NCBI
21	White CD, Brown MD and Sacks DB: IQGAPs in cancer: A family of scaffold proteins underlying tumorigenesis. FEBS Lett. 583:1817–1824. 2009. View Article : Google Scholar : PubMed/NCBI
22	Detmar M: Tumor angiogenesis. J Investig Dermatol Symp Proc. 5:20–23. 2000. View Article : Google Scholar : PubMed/NCBI
23	Shibuya M: Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2:1097–1105. 2011. View Article : Google Scholar : PubMed/NCBI
24	McMahon G: VEGF receptor signaling in tumor angiogenesis. Oncologist. 5 Suppl 1:S3–S10. 2000. View Article : Google Scholar
25	Yamaoka-Tojo M, Tojo T, Kim HW, Hilenski L, Patrushev NA, Zhang L, Fukai T and Ushio-Fukai M: IQGAP1 mediates VE-cadherin-based cell-cell contacts and VEGF signaling at adherence junctions linked to angiogenesis. Arterioscler Thromb Vasc Biol. 26:1991–1997. 2006. View Article : Google Scholar : PubMed/NCBI
26	Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L, Dikalov SI, Chen YE, Tojo T, Fukai T, Fujimoto M, Patrushev NA, Wang N, et al: IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species-dependent endothelial migration and proliferation. Circ Res. 95:276–283. 2004. View Article : Google Scholar : PubMed/NCBI
27	Meyer RD, Sacks DB and Rahimi N: IQGAP1-dependent signaling pathway regulates endothelial cell proliferation and angiogenesis. PLoS One. 3:e38482008. View Article : Google Scholar : PubMed/NCBI
28	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI
29	Jiang BH and Liu LZ: AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets. 8:19–26. 2008. View Article : Google Scholar : PubMed/NCBI
30	Dhillon AS, Hagan S, Rath O and Kolch W: MAP kinase signalling pathways in cancer. Oncogene. 26:3279–3290. 2007. View Article : Google Scholar : PubMed/NCBI
31	Ding C, Li L, Yang T, Fan X and Wu G: Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model. BMC Cancer. 16:7912016. View Article : Google Scholar : PubMed/NCBI
32	Sbroggiò M, Carnevale D, Bertero A, Cifelli G, De Blasio E, Mascio G, Hirsch E, Bahou WF, Turco E, Silengo L, et al: IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload. Cardiovasc Res. 91:456–464. 2011. View Article : Google Scholar : PubMed/NCBI
33	Chen F, Zhu HH, Zhou LF, Wu SS, Wang J and Chen Z: IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med. 42:477–483. 2010. View Article : Google Scholar : PubMed/NCBI
34	Ma Y, Jin Z, Huang J, Zhou S, Ye H, Jiang S and Yu K: IQGAP1 plays an important role in the cell proliferation of multiple myeloma via the MAP kinase (ERK) pathway. Oncol Rep. 30:3032–3038. 2013. View Article : Google Scholar : PubMed/NCBI
35	Cheung KL, Lee JH, Shu L, Kim JH, Sacks DB and Kong AN: The Ras GTPase-activating-like protein IQGAP1 mediates Nrf2 protein activation via the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway. J Biol Chem. 288:22378–22386. 2013. View Article : Google Scholar : PubMed/NCBI