Silencing FOXC1 inhibits growth and migration of human oral squamous cell carcinoma cells

Liu,Zhongjun; Xu,Shuaimei; Chu,Hongxing; Lu,Yu; Yuan,Peiyan; Zeng,Xiongqun

doi:10.3892/etm.2018.6627

Silencing FOXC1 inhibits growth and migration of human oral squamous cell carcinoma cells

Authors:
- Zhongjun Liu
- Shuaimei Xu
- Hongxing Chu
- Yu Lu
- Peiyan Yuan
- Xiongqun Zeng
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Affiliations: Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China, Department of Oral and Maxillofacial Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
Published online on: August 20, 2018 https://doi.org/10.3892/etm.2018.6627
Pages: 3369-3376
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Forkhead box C1 (FOXC1) is a transcription factor that serves an important role in regulating tumorigenesis and cancer progression. However, the expression and functional role of FOXC1 in oral squamous cell carcinoma (OSCC) remains unclear. FOXC1 protein expression was determined using immunohistochemical staining of OSCC tissues and normal tissues. Cell Counting Kit‑8, colony formation, migration and 5‑ethynyl‑2'‑deoxyuridine assays were performed to investigate the role and underlying mechanism of action of FOXC1 in OSCC. A consistent increase in the immunoreactive intensity of FOXC1 in OSCC tissues as compared with that in adjacent normal tissues was demonstrated. Knockdown of FOXC1 impaired cell growth and colony formation by inhibiting cell proliferation and reducing cyclin B1 and cyclin D1 levels in OSCC cells. FOXC1‑silenced OSCC cells exhibited decreased migration compared with that demonstrated by the control cells, accompanied by a downregulation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Collectively, the results of the present study demonstrated that FOXC1 functions as an oncogene in OSCC and may be an important therapeutic target and predictive biomarker for OSCC.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2	Choi S and Myers JN: Molecular pathogenesis of oral squamous cell carcinoma: Implications for therapy. J Dent Res. 87:14–32. 2008. View Article : Google Scholar : PubMed/NCBI
3	Abram MH, van Heerden WF, Rheeder P, Girdler-Brown BV and van Zyl AW: Epidemiology of oral squamous cell carcinoma. SADJ. 67:550–553. 2012.PubMed/NCBI
4	Fuller CD, Wang SJ, Thomas CR Jr, Hoffman HT, Weber RS and Rosenthal DI: Conditional survival in head and neck squamous cell carcinoma: Results from the SEER dataset 1973–1998. Cancer. 109:1331–1343. 2007. View Article : Google Scholar : PubMed/NCBI
5	Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC, Krantz ID, Dobyns WB and Millen KJ: FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 41:1037–1042. 2009. View Article : Google Scholar : PubMed/NCBI
6	Lin YJ, Shyu WC, Chang CW, Wang CC, Wu CP, Lee HT, Chen LJ and Hsieh CH: Tumor hypoxia regulates forkhead box C1 to promote lung cancer progression. Theranostics. 7:1177–1191. 2017. View Article : Google Scholar : PubMed/NCBI
7	Wang L, Chai L, Ji Q, Cheng R, Wang J and Han S: Forkhead box protein C1 promotes cell proliferation and invasion in human cervical cancer. Mol Med R. 17:4392–4398. 2018.
8	Ou-Yang L, Xiao SJ, Liu P, Yi SJ, Zhang XL, Ou-Yang S, Tan SK and Lei X: Forkhead box C1 induces epithelial-mesenchymal transition and is a potential therapeutic target in nasopharyngeal carcinoma. Mol Med Rep. 12:8003–8009. 2015. View Article : Google Scholar : PubMed/NCBI
9	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
10	Dai L, Cui X, Zhang X, Cheng L, Liu Y, Yang Y, Fan P, Wang Q, Lin Y, Zhang J, et al: SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin. Nat Commun. 7:119962016. View Article : Google Scholar : PubMed/NCBI
11	Berry FB, Saleem RA and Walter MA: FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain. J Biol Chem. 277:10292–10297. 2002. View Article : Google Scholar : PubMed/NCBI
12	Xia L, Huang W, Tian D, Zhu H, Qi X, Chen Z, Zhang Y, Hu H, Fan D, Nie Y and Wu K: Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 57:610–624. 2013. View Article : Google Scholar : PubMed/NCBI
13	Xu ZY, Ding SM, Zhou L, Xie HY, Chen KJ, Zhang W, Xing CY, Guo HJ and Zheng SS: FOXC1 contributes to microvascular invasion in primary hepatocellular carcinoma via regulating epithelial-mesenchymal transition. Int J Biol Sci. 8:1130–1141. 2012. View Article : Google Scholar : PubMed/NCBI
14	Huang W, Chen Z, Zhang L, Tian D, Wang D, Fan D, Wu K and Xia L: Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice. Gastroenterology. 149:1053–1067.e1014. 2015. View Article : Google Scholar : PubMed/NCBI
15	Wang L, Gu F, Liu CY, Wang RJ, Li J and Xu JY: High level of FOXC1 expression is associated with poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 34:853–858. 2013. View Article : Google Scholar : PubMed/NCBI
16	Xu Y, Shao QS, Yao HB, Jin Y, Ma YY and Jia LH: Overexpression of FOXC1 correlates with poor prognosis in gastric cancer patients. Histopathology. 64:963–970. 2014. View Article : Google Scholar : PubMed/NCBI
17	Nishimura DY, Searby CC, Alward WL, Walton D, Craig JE, Mackey DA, Kawase K, Kanis AB, Patil SR, Stone EM and Sheffield VC: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet. 68:364–372. 2001. View Article : Google Scholar : PubMed/NCBI
18	Tanwar M, Kumar M, Dada T, Sihota R and Dada R: MYOC and FOXC1 gene analysis in primary congenital glaucoma. Mol Vis. 16:1996–2006. 2010.PubMed/NCBI
19	Hayashi H and Kume T: Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migration. Biochem Biophys Res Commun. 367:584–589. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP, Ye X, Liu B, Elashoff D, Hoon DS, et al: FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res. 70:3870–3876. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zhou M, Ye Z, Gu Y, Tian B, Wu B and Li J: Genomic analysis of drug resistant pancreatic cancer cell line by combining long non-coding RNA and mRNA expression profling. Int J Clin Exp Pathol. 8:38–52. 2015.PubMed/NCBI
22	Strizzi L, Bianco C, Normanno N, Seno M, Wechselberger C, Wallace-Jones B, Khan NI, Hirota M, Sun Y, Sanicola M and Salomon DS: Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J Cell Physiol. 201:266–276. 2004. View Article : Google Scholar : PubMed/NCBI
23	Lambers E, Arnone B, Fatima A, Qin G, Wasserstrom JA and Kume T: Foxc1 regulates early cardiomyogenesis and functional properties of embryonic stem cell derived cardiomyocytes. Stem Cells. 34:1487–1500. 2016. View Article : Google Scholar : PubMed/NCBI
24	Lin Z, Sun L, Chen W, Liu B, Wang Y, Fan S, Li Y and Li J: miR-639 regulates transforming growth factor beta-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting FOXC1. Cancer Sci. 105:1288–1298. 2014. View Article : Google Scholar : PubMed/NCBI
25	Medina-Trillo C, Aroca-Aguilar JD, Ferre-Fernandez JJ, Méndez-Hernández CD, Morales L, García-Feijoo J and Escribano J: The role of hsa-miR-548l dysregulation as a putative modifier factor for glaucoma-associated FOXC1 mutations. Microrna. 4:50–56. 2015. View Article : Google Scholar : PubMed/NCBI
26	Jin Y, Han B, Chen J, Wiedemeyer R, Orsulic S, Bose S, Zhang X, Karlan BY, Giuliano AE, Cui Y and Cui X: FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer. Ann Surg Oncol. 21 Suppl 4:S758–S766. 2014. View Article : Google Scholar : PubMed/NCBI
27	Hopkins A, Mirzayans F and Berry F: Foxc1 expression in early osteogenic differentiation is regulated by BMP4-SMAD activity. J Cell Biochem. 117:1707–1717. 2016. View Article : Google Scholar : PubMed/NCBI