IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways. The accumulating evidence has demonstrated that IQGAP1 plays an important role in tumorigenesis and tumor progression. However, the function of IQGAP1 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly investigated. In the present study, we showed that IQGAP1 was overexpressed in ESCC tumor tissues, and its overexpression was correlated with the invasion depth of ESCC. Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice. Furthermore, Knockdown of IQGAP1 expression in ESCC cell lines led to a reversion of epithelial to mesenchymal transition (EMT) progress. These results suggest that IQGAP1 plays crucial roles in regulating ESCC occurrence and progression. IQGAP1 silencing may therefore develop into a promising novel anticancer therapy.
References
[1]
Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, et al. (2013) Epidemiology of esophageal cancer in Japan and China. J Epidemiol 23: 233–242. doi: 10.2188/jea.je20120162
Lin DC, Du XL, Wang MR (2009) Protein alterations in ESCC and clinical implications: a review. Dis Esophagus 22: 9–20. doi: 10.1111/j.1442-2050.2008.00845.x
[4]
White CD, Erdemir HH, Sacks DB (2012) IQGAP1 and its binding proteins control diverse biological functions. Cell Signal 24: 826–834. doi: 10.1016/j.cellsig.2011.12.005
[5]
Johnson M, Sharma M, Henderson BR (2009) IQGAP1 regulation and roles in cancer. Cell Signal 21: 1471–1478. doi: 10.1016/j.cellsig.2009.02.023
[6]
White CD, Brown MD, Sacks DB (2009) IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett 583: 1817–1824. doi: 10.1016/j.febslet.2009.05.007
[7]
Noritake J, Watanabe T, Sato K, Wang S, Kaibuchi K (2005) IQGAP1: a key regulator of adhesion and migration. J Cell Sci 118: 2085–2092. doi: 10.1242/jcs.02379
[8]
Kim H, White CD, Sacks DB (2011) IQGAP1 in microbial pathogenesis: Targeting the actin cytoskeleton. FEBS Lett 585: 723–729. doi: 10.1016/j.febslet.2011.01.041
[9]
Osman M (2010) An emerging role for IQGAP1 in regulating protein traffic. Scientific World Journal 10: 944–953. doi: 10.1100/tsw.2010.85
[10]
Liu Z, Liu D, Bojdani E, El-Naggar AK, Vasko V, et al. (2010) IQGAP1 plays an important role in the invasiveness of thyroid cancer. Clin Cancer Res 16: 6009–6018. doi: 10.1158/1078-0432.ccr-10-1627
[11]
Dong PX, Jia N, Xu ZJ, Liu YT, Li DJ, et al. (2008) Silencing of IQGAP1 by shRNA inhibits the invasion of ovarian carcinoma HO-8910PM cells in vitro. J Exp Clin Cancer Res 27: 77–82. doi: 10.1186/1756-9966-27-77
[12]
Briggs MW, Li Z, Sacks DB (2002) IQGAP1-mediated stimulation of transcriptional co-activation by beta-catenin is modulated by calmodulin. J Biol Chem 277: 7453–7465. doi: 10.1074/jbc.m104315200
[13]
Wang Y, Wang A, Wang F, Wang M, Zhu M, et al. (2008) IQGAP1 activates Tcf signal independent of Rac1 and Cdc42 in injury and repair of bronchial epithelial cells. Exp Mol Pathol 85: 122–128. doi: 10.1016/j.yexmp.2008.06.001
[14]
Hayashi H, Nabeshima K, Aoki M, Hamasaki M, Enatsu S, et al. (2010) Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion. Int J Cancer 126: 2563–2574. doi: 10.1002/ijc.24987
[15]
Nabeshima K, Shimao Y, Inoue T, Koono M (2002) Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts. Cancer Lett 176: 101–109. doi: 10.1016/s0304-3835(01)00742-x
[16]
Takemoto H, Doki Y, Shiozaki H, Imamura H, Utsunomiya T, et al. (2001) Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by e-cadherin in gastric cancers. Int J Cancer 91: 783–788. doi: 10.1002/1097-0215(200002)9999:9999<::aid-ijc1121>3.0.co;2-z
[17]
Walch A, Seidl S, Hermannst？dter C, Rauser S, Deplazes J, et al. (2008) Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. Mod Pathol 21: 544–552. doi: 10.1038/modpathol.2008.3
[18]
White CD, Khurana H, Gnatenko DV, Li Z, Odze RD, et al. (2010) IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma. BMC Gastroenterol 10: 125–134. doi: 10.1186/1471-230x-10-125
[19]
Chen F, Zhu HH, Zhou LF, Wu SS, Wang J, et al. (2010) IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med 42: 477–483. doi: 10.3858/emm.2010.42.7.049
[20]
Wang XX, Li XZ, Zhai LQ, Liu ZR, Chen XJ, et al. (2013) Overexpression of IQGAP1 in human pancreatic cancer. Hepatobiliary Pancreat Dis Int 12: 540–545. doi: 10.1016/s1499-3872(13)60085-5
[21]
Dong P, Nabeshima K, Nishimura N, Kawakami T, Hachisuga T, et al. (2006) Overexpression and diffuse expression pattern of IQGAP1 at invasion fronts are independent prognostic parameters in ovarian carcinomas. Cancer Lett 243: 120–127. doi: 10.1016/j.canlet.2005.11.024
[22]
Wu Y, Tao Y, Chen Y, Xu W (2012) RhoC regulates the proliferation of gastric cancer cells through interaction with IQGAP1. PLoS One 7(11): e48917. doi: 10.1371/journal.pone.0048917
[23]
Jadeski L, Mataraza JM, Jeong HW, Li Z, Sacks DB (2008) IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem 283: 1008–1017. doi: 10.1074/jbc.m708466200
[24]
Guarino M, Tosoni A, Nebuloni M (2009) Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Hum Pathol 40: 1365–1376.
[25]
Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, et al. (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213: 374–383. doi: 10.1002/jcp.21223
[26]
Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci. 121: 727–735. doi: 10.1242/jcs.000455
[27]
Kuroda S, Fukata M, Nakagawa M, Fujii K, Nakamura T, et al. (1998) Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion. Science 281: 832–835. doi: 10.1126/science.281.5378.832
