Frizzled2 mediates the migration and invasion of human oral squamous cell carcinoma cells through the regulation of the signal transducer and activator of transcription-3 signaling pathway

Zhang,Enjiao; Li,Zhenning; Xu,Zhongfei; Duan,Weiyi; Sun,Changfu; Lu,Li

doi:10.3892/or.2015.4285

Frizzled2 mediates the migration and invasion of human oral squamous cell carcinoma cells through the regulation of the signal transducer and activator of transcription-3 signaling pathway

Authors:
- Enjiao Zhang
- Zhenning Li
- Zhongfei Xu
- Weiyi Duan
- Changfu Sun
- Li Lu
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Affiliations: Department of Oral and Maxillofacial Surgery, Department of Oromaxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
Published online on: September 17, 2015 https://doi.org/10.3892/or.2015.4285
Pages: 3061-3067

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Abstract

Frizzled2 (Fzd2) is a receptor for wingless-type MMTV integration site family members (Wnts), the aberrant overexpression of which has been noted to contribute to cancer metastasis. The present study was performed to characterize the role of Fzd2 in the migration and invasion of oral squamous cell carcinomas (OSCC) in vitro. Using TSCCa cells (a tongue SCC cell line) for loss- or gain-of-function of Fzd2, we found that a forced overexpression of Fzd2 promoted TSCCa cell migration and invasion, decreased the expression of epithelial‑cadherin (E-cadherin, an epithelial marker) and increased that of vimentin, Snail Slug, matrix metalloproteinases (MMPs)-2/-9/-13 and a-disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5). By contrast, RNA interference (RNAi)-mediated knockdown of Fzd2 had opposite effects on OSCC cells. In addition, we found that the phosphorylation of signal transducer and activator of transcription-3 (STAT3) was enhanced by Fzd2 overexpression, but suppressed by Fzd2 depletion, and that STAT3‑specific shRNA attenuated Fzd2 overexpression‑induced cell invasion. In summary, the present study demonstrated that Fzd2 contributes to the migration and invasion of OSCC cells, at least partly through regulation of the STAT3 pathway. These results suggest Fzd2 as a novel therapeutic target for OSCC.

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1	Knopf A, Lempart J, Bas M, Slotta-Huspenina J, Mansour N and Fritsche MK: Oncogenes and tumor suppressor genes in squamous cell carcinoma of the tongue in young patients. Oncotarget. 6:3443–3451. 2015. View Article : Google Scholar : PubMed/NCBI
2	Taguchi T, Nishimura G, Takahashi M, Komatsu M, Sano D, Sakuma N, Arai Y, Yamashita Y, Shiono O, Hirama M, et al: Treatment results and prognostic factors for advanced squamous cell carcinoma of the larynx treated with concurrent chemoradiotherapy. Cancer Chemother Pharmacol. 72:837–843. 2013. View Article : Google Scholar : PubMed/NCBI
3	Zitelli KB, Zedek D, Ranganathan P and Amerson EH: Squamous cell carcinoma of the lip associated with adalimumab therapy for ankylosing spondylitis: A case report and review of TNF-α inhibitors and cutaneous carcinoma risk. Cutis. 92:35–39. 2013.PubMed/NCBI
4	Dionne KR, Warnakulasuriya S, Zain RB and Cheong SC: Potentially malignant disorders of the oral cavity: Current practice and future directions in the clinic and laboratory. Int J Cancer. 136:503–515. 2015.
5	Wenig BM: Squamous cell carcinoma of the upper aerodigestive tract: Precursors and problematic variants. Mod Pathol. 15:229–254. 2002. View Article : Google Scholar : PubMed/NCBI
6	Han S, Chen Y, Ge X, Zhang M, Wang J, Zhao Q, He J and Wang Z: Epidemiology and cost analysis for patients with oral cancer in a university hospital in China. BMC Public Health. 10:1962010. View Article : Google Scholar : PubMed/NCBI
7	Fury MG, Xiao H, Sherman EJ, Baxi S, Smith-Marrone S, Schupak K, Gewanter R, Gelblum D, Haque S, Schoder H, et al: A phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity modulated radiation therapy (IMRT) for patients with stage III/IVB head and neck squamous cell carcinoma (HNSCC). Head Neck. Mar 17–2015.Epub ahead of print. View Article : Google Scholar
8	Simpson DR, Mell LK and Cohen EE: Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 51:291–298. 2015. View Article : Google Scholar
9	Sagara N, Toda G, Hirai M, Terada M and Katoh M: Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7. Biochem Biophys Res Commun. 252:117–122. 1998. View Article : Google Scholar : PubMed/NCBI
10	Peifer M and Polakis P: Wnt signaling in oncogenesis and embryogenesis - a look outside the nucleus. Science. 287:1606–1609. 2000. View Article : Google Scholar : PubMed/NCBI
11	Ueno K, Hirata H, Hinoda Y and Dahiya R: Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. Int J Cancer. 132:1731–1740. 2013. View Article : Google Scholar
12	Lee HC, Kim M and Wands JR: Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci. 11:1901–1915. 2006. View Article : Google Scholar
13	Hlubek F, Spaderna S, Schmalhofer O, Jung A, Kirchner T and Brabletz T: Wnt/FZD signaling and colorectal cancer morphogenesis. Front Biosci. 12:458–470. 2007. View Article : Google Scholar
14	Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, et al: Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA. 109:11717–11722. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ding LC, Huang XY, Zheng FF, Xie J, She L, Feng Y, Su BH, Zheng DL and Lu YG: FZD2 inhibits the cell growth and migration of salivary adenoid cystic carcinomas. Oncol Rep. Feb 19–2015.Epub ahead of print. View Article : Google Scholar
16	Rhee CS, Sen M, Lu D, Wu C, Leoni L, Rubin J, Corr M and Carson DA: Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene. 21:6598–6605. 2002. View Article : Google Scholar : PubMed/NCBI
17	Prgomet Z, Axelsson L, Lindberg P and Andersson T: Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression. J Oral Pathol Med. Dec 2–2014.Epub ahead of print. PubMed/NCBI
18	Schefe JH, Lehmann KE, Buschmann IR, Unger T and Funke-Kaiser H: Quantitative real-time RT-PCR data analysis: Current concepts and the novel 'gene expression's CT difference' formula. J Mol Med Berl. 84:901–910. 2006. View Article : Google Scholar
19	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
20	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
21	van Goor H, Melenhorst WB, Turner AJ and Holgate ST: Adamalysins in biology and disease. J Pathol. 219:277–286. 2009. View Article : Google Scholar : PubMed/NCBI
22	Bonnans C, Chou J and Werb Z: Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 15:786–801. 2014. View Article : Google Scholar : PubMed/NCBI
23	Mochizuki S and Okada Y: ADAMs in cancer cell proliferation and progression. Cancer Sci. 98:621–628. 2007. View Article : Google Scholar : PubMed/NCBI
24	Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI
25	Díaz Prado SM, Medina Villaamil V, Aparicio Gallego G, Blanco Calvo M, López Cedrún JL, Sironvalle Soliva S, Valladares Ayerbes M, García Campelo R and Antón Aparicio LM: Expression of Wnt gene family and frizzled receptors in head and neck squamous cell carcinomas. Virchows Arch. 455:67–75. 2009. View Article : Google Scholar : PubMed/NCBI
26	Sano D and Myers JN: Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev. 26:645–662. 2007. View Article : Google Scholar : PubMed/NCBI
27	Zhang YX, Yu SB, Ou-Yang JP, Xia D, Wang M and Li JR: Effect of protein kinase C alpha, caspase-3, and survivin on apoptosis of oral cancer cells induced by staurosporine. Acta Pharmacol Sin. 26:1365–1372. 2005. View Article : Google Scholar : PubMed/NCBI
28	Yilmaz M and Christofori G: EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28:15–33. 2009. View Article : Google Scholar : PubMed/NCBI
29	Huang RY, Guilford P and Thiery JP: Early events in cell adhesion and polarity during epithelial-mesenchymal transition. J Cell Sci. 125:4417–4422. 2012. View Article : Google Scholar : PubMed/NCBI
30	Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW and MacBeath G: A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell. 159:844–856. 2014. View Article : Google Scholar : PubMed/NCBI
31	Orgaz JL, Pandya P, Dalmeida R, Karagiannis P, Sanchez-Laorden B, Viros A, Albrengues J, Nestle FO, Ridley AJ, Gaggioli C, et al: Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat Commun. 5:42552014. View Article : Google Scholar : PubMed/NCBI
32	Chiang WC, Wong YK, Lin SC, Chang KW and Liu CJ: Increase of MMP-13 expression in multi-stage oral carcinogenesis and epigallocatechin-3-gallate suppress MMP-13 expression. Oral Dis. 12:27–33. 2006. View Article : Google Scholar : PubMed/NCBI
33	Henriques AC, de Matos FR, Galvão HC and Freitas RA: Immunohistochemical expression of MMP-9 and VEGF in squamous cell carcinoma of the tongue. J Oral Sci. 54:105–111. 2012. View Article : Google Scholar : PubMed/NCBI
34	Ruokolainen H, Pääkkö P and Turpeenniemi-Hujanen T: Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma - tissue immunoreactivity predicts aggressive clinical course. Mod Pathol. 19:208–217. 2006. View Article : Google Scholar : PubMed/NCBI
35	Filou S, Stylianou M, Triantaphyllidou IE, Papadas T, Mastronikolis NS, Goumas PD, Papachristou DJ, Ravazoula P, Skandalis SS and Vynios DH: Expression and distribution of aggrecanases in human larynx: ADAMTS-5/aggrecanase-2 is the main aggrecanase in laryngeal carcinoma. Biochimie. 95:725–734. 2013. View Article : Google Scholar
36	Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN and Aaronson SA: Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev. 24:2517–2530. 2010. View Article : Google Scholar : PubMed/NCBI