IQGAP1 modulates the proliferation and invasion of thyroid cancer cells in response to estrogen

Meng,Dongdong; Wu,Wenxun; Li,Zhifu; Qin,Guijun

doi:10.3892/ijmm.2015.2232

IQGAP1 modulates the proliferation and invasion of thyroid cancer cells in response to estrogen

Authors:
- Dongdong Meng
- Wenxun Wu
- Zhifu Li
- Guijun Qin
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Affiliations: Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: June 3, 2015 https://doi.org/10.3892/ijmm.2015.2232
Pages: 588-594

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Abstract

Thyroid cancer is an endocrine malignancy with a high incidence rate, which is affected by female hormones, particularly estrogens, in its growth and progression. IQ-domain GTPase‑activating protein 1 (IQGAP1) is overexpressed in a range of types of cancer and is reported to interact with estrogen receptor α (ERα) in breast cancer cells. However, the association between IQGAP1 and ERα in thyroid cancer cells remains to be elucidated. In this study, the role of IQGAP1 in thyroid cancer cells was examined. The expression of IQGAP1 (190 kDa) was analyzed using western blot analysis, which indicated that IQGAP1 was overexpressed in thyroid cancer tissues and FTC133 cells. However, IQGAP1 knockdown in the FTC133 cells led to a significant downregulation in ERα transcriptional activity, cell proliferation, cell adhesion and cell invasion under 17β‑estradiol (E2) conditions. Furthermore, ERα knockdown inhibited the enhanced protein expression levels of phosphorylated ERK1/2 and cyclin D1, which were induced by the overexpression of IQGAP1. Co‑immunoprecipitation wasalso performed in thyroid cancer cells and the results suggested that IQGAP1 directly interacted with ERα in the FTC133 cells and the co‑transfected COS‑7 cells. Taken together, these findings revealed that IQGAP1 may directly interact with ERα and serve as a signal integrator, mediating ERα transcriptional activity, cell proliferation and cell invasion during the progression of thyroid cancer.

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1	Kumar A, Klinge CM and Goldstein RE: Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors α and β. Int J Oncol. 36:1067–1080. 2010.PubMed/NCBI
2	Thomas C and Gustafsson JA: The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 11:597–608. 2011. View Article : Google Scholar : PubMed/NCBI
3	Heldring N, Pike A, Andersson S, et al: Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 87:905–931. 2007. View Article : Google Scholar : PubMed/NCBI
4	Erdemir HH, Li Z and Sacks DB: IQGAP1 binds to estrogen receptor-α and modulates its function. J Biol Chem. 289:9100–9112. 2014. View Article : Google Scholar : PubMed/NCBI
5	Brown MD and Sacks DB: IQGAP1 in cellular signaling: bridging the GAP. Trends Cell Biol. 16:242–249. 2006. View Article : Google Scholar : PubMed/NCBI
6	Machesky LM: Cytokinesis: IQGAPs find a function. Curr Biol. 8:R202–R205. 1998. View Article : Google Scholar : PubMed/NCBI
7	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
8	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 :
9	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
10	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
11	Sugimoto N, Imoto I, Fukuda Y, et al: IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. J Hum Genet. 46:21–25. 2001. View Article : Google Scholar : PubMed/NCBI
12	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
13	Dong P, Nabeshima K, Nishimura N, et al: 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
14	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
15	Chen Z, Gibson TB, Robinson F, et al: MAP kinases. Chem Rev. 101:2449–2476. 2001. View Article : Google Scholar : PubMed/NCBI
16	Schaeffer HJ and Weber MJ: Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol. 19:2435–2444. 1999.PubMed/NCBI
17	Thrane S, Lykkesfeldt AE, Larsen MS, Sorensen BS and Yde CW: Estrogen receptor α is the major driving factor for growth in tamoxifen-resistant breast cancer and supported by HER/ERK signaling. Breast Cancer Res Treat. 139:71–80. 2013. View Article : Google Scholar : PubMed/NCBI
18	Walter P, Green S, Greene G, et al: Cloning of the human estrogen receptor cDNA. Proc Natl Acad Sci USA. 82:7889–7893. 1985. View Article : Google Scholar : PubMed/NCBI
19	Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 93:5925–5930. 1996. View Article : Google Scholar : PubMed/NCBI
20	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
21	Mirebeau-Prunier D, Le Pennec S, Jacques C, et al: Estrogen-related receptor alpha and PGC-1-related coactivator constitute a novel complex mediating the biogenesis of functional mitochondria. FEBS J. 277:713–725. 2010. View Article : Google Scholar : PubMed/NCBI
22	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
23	Ma Y, Jin Z, Huang J, et al: IQGAP1 plays an important role in the cell proliferation of multiple myeloma via the MAP kinase (ERK) pathway. Oncol Rep. 30:3032–3038. 2013.PubMed/NCBI
24	Wang XX, Wang K, Li XZ, 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
25	Safe S: Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm. 62:231–252. 2001. View Article : Google Scholar : PubMed/NCBI
26	Cavarretta IT, Mukopadhyay R, Lonard DM, et al: Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation. Mol Endocrinol. 16:253–270. 2002.PubMed/NCBI
27	Nilsson UW, Garvin S and Dabrosin C: MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat. 102:253–261. 2007. View Article : Google Scholar
28	Kousidou OC, Berdiaki A, Kletsas D, et al: Estradiol-estrogen receptor: a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cells. Mol Oncol. 2:223–232. 2008. View Article : Google Scholar
29	Rajoria S, Suriano R, George A, et al: Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3′-diindolyl-methane in thyroid cancer. PLoS One. 6:e158792011. View Article : Google Scholar
30	Graff JR, Greenberg VE, Herman JG, et al: Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle’s cell, and poorly differentiated human thyroid carcinoma. Cancer Res. 58:2063–2066. 1998.PubMed/NCBI
31	Shiozaki H, Oka H, Inoue M, Tamura S and Monden M: E-cadherin mediated adhesion system in cancer cells. Cancer. 77:1605–1613. 1996. View Article : Google Scholar : PubMed/NCBI
32	Mataraza JM, Briggs MW, Li Z, Entwistle A, Ridley AJ and Sacks DB: IQGAP1 promotes cell motility and invasion. J Biol Chem. 278:41237–41245. 2003. View Article : Google Scholar : PubMed/NCBI
33	Watanabe T, Wang S, Noritake J, et al: Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell. 7:871–883. 2004. View Article : Google Scholar : PubMed/NCBI
34	Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L, et al: IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species - dependent endo-thelial migration and proliferation. Circ Res. 95:276–283. 2004. View Article : Google Scholar : PubMed/NCBI
35	Fukata M, Kuroda S, Nakagawa M, et al: Cdc42 and Rac1 regulate the interaction of IQGAP1 with beta-catenin. J Biol Chem. 274:26044–26050. 1999. View Article : Google Scholar : PubMed/NCBI
36	Wu TW, Wang JM, Chen S and Brinton RD: 17Beta-estradiol induced Ca²⁺ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience. 135:59–72. 2005. View Article : Google Scholar
37	Acconcia F, Ascenzi P, Bocedi A, et al: Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell. 16:231–237. 2005. View Article : Google Scholar :
38	Marino M, Acconcia F, Bresciani F, Weisz A and Trentalance A: Distinct nongenomic signal transduction pathways controlled by 17beta-estradiol regulate DNA synthesis and cyclin D(1) gene transcription in HepG2 cells. Mol Biol Cell. 13:3720–3729. 2002. View Article : Google Scholar : PubMed/NCBI
39	Marino M, Acconcia F and Trentalance A: Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell. 14:2583–2591. 2003. View Article : Google Scholar : PubMed/NCBI