FOXC1 silencing inhibits the epithelial‑to‑mesenchymal transition of glioma cells: Involvement of β‑catenin signaling

Cao,Qinchen; Wang,Xinxin; Shi,Yonggang; Zhang,Mingzhi; Yang,Jing; Dong,Meilian; Mi,Yin; Zhang,Zhigang; Liu,Ke; Jiang,Li; Wang,Na; Wang,Ping

doi:10.3892/mmr.2018.9650

FOXC1 silencing inhibits the epithelial‑to‑mesenchymal transition of glioma cells: Involvement of β‑catenin signaling

Authors:
- Qinchen Cao
- Xinxin Wang
- Yonggang Shi
- Mingzhi Zhang
- Jing Yang
- Meilian Dong
- Yin Mi
- Zhigang Zhang
- Ke Liu
- Li Jiang
- Na Wang
- Ping Wang
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Affiliations: Department of Radiation Therapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Radiation Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
Published online on: November 13, 2018 https://doi.org/10.3892/mmr.2018.9650
Pages: 251-261
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioma is a type of malignant brain tumor. Forkhead box C1 (FOXC1) is a conserved transcription factor that is involved in tumorigenesis; however, the function of FOXC1 in glioma remains unclear. The present study aimed to investigate the effects of FOXC1 silencing on the epithelial‑to‑mesenchymal transition (EMT) of glioma cells. FOXC1‑specific small interfering RNAs were employed to downregulate the expression levels of FOXC1 in glioma cells. The proliferation, migration and invasion of glioma cells were assessed by MTT assay, wound healing assay and Transwell assay. Western blot analysis was performed to reveal the effects of FOXC1 on EMT‑associated proteins and β‑catenin signaling. The results revealed that, following FOXC1 silencing, the proliferation, migration and invasion of glioma cells were decreased. The expression levels of EMT‑associated proteins were also affected. Further examination demonstrated that β‑catenin signaling was involved in the effects of FOXC1 on glioma cells. Previous results suggested that overexpression of β‑catenin reversed the effects of FOXC1 silencing on glioma cells. The present study demonstrated that FOXC1 may regulate the EMT of glioma cells, potentially via β‑catenin signaling. Therefore, FOXC1 may be a potential therapeutic target for the treatment of glioma.

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1	Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the united states in 2008-2012. Neuro Oncol. 4 Suppl 17:iv1–iv62. 2015. View Article : Google Scholar
2	Ho VK, Reijneveld JC, Enting RH, Bienfait HP, Robe P, Baumert BG and Visser O; Dutch Society for Neuro-Oncology (LWNO), : Changing incidence and improved survival of gliomas. Eur J Cancer. 50:2309–2318. 2014. View Article : Google Scholar : PubMed/NCBI
3	Brabletz T, Kalluri R, Nieto MA and Weinberg RA: EMT in cancer. Nat Rev Cancer. 18:128–134. 2018. View Article : Google Scholar : PubMed/NCBI
4	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
5	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
7	Han B, Bhowmick N, Qu Y, Chung S, Giuliano AE and Cui X: FOXC1: An emerging marker and therapeutic target for cancer. Oncogene. 36:3957–3963. 2017. View Article : Google Scholar : PubMed/NCBI
8	Seo S, Fujita H, Nakano A, Kang M, Duarte A and Kume T: The forkhead transcription factors, foxc1 and foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol. 294:458–470. 2006. View Article : Google Scholar : PubMed/NCBI
9	Sun J, Ishii M, Ting MC and Maxson R: Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2. Development. 140:1034–1044. 2013. View Article : Google Scholar : PubMed/NCBI
10	Bin L, Deng L, Yang H, Zhu L, Wang X, Edwards MG, Richers B and Leung DY: Forkhead box C1 regulates human primary keratinocyte terminal differentiation. PLoS One. 11:e01673922016. View Article : Google Scholar : PubMed/NCBI
11	Mirzayans F, Lavy R, Penner-Chea J and Berry FB: Initiation of early osteoblast differentiation events through the direct transcriptional regulation of Msx2 by FOXC1. PLoS One. 7:e490952012. View Article : Google Scholar : PubMed/NCBI
12	Wang J, Xu Y, Li L, Wang L, Yao R, Sun Q and Du G: FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer. Cancer Med. 6:275–287. 2017. View Article : Google Scholar : PubMed/NCBI
13	Sizemore ST and Keri RA: The forkhead box transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J Biol Chem. 287:24631–24640. 2012. View Article : Google Scholar : PubMed/NCBI
14	Wei LX, Zhou RS, Xu HF, Wang JY and Yuan MH: High expression of FOXC1 is associated with poor clinical outcome in non-small cell lung cancer patients. Tumour Biol. 34:941–946. 2013. View Article : Google Scholar : PubMed/NCBI
15	Chen S, Jiao S, Jia Y and Li Y: Effects of targeted silencing of FOXC1 gene on proliferation and in vitro migration of human non-small-cell lung carcinoma cells. Am J Transl Res. 8:3309–3318. 2016.PubMed/NCBI
16	Wang J, Ray PS, Sim MS, Zhou XZ, Lu KP, Lee AV, Lin X, Bagaria SP, Giuliano AE and Cui X: FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-kB signaling. Oncogene. 31:4798–4802. 2012. View Article : Google Scholar : PubMed/NCBI
17	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
18	Ou-Yang L, Xiao SJ, Liu P, Yi SJ, Zhang XL, Ou-Yang S, Tan SK and Lei X: Forkhead box C1 induces epithelialmesenchymal transition and is a potential therapeutic target in nasopharyngeal carcinoma. Mol Med Rep. 12:8003–8009. 2015. View Article : Google Scholar : PubMed/NCBI
19	Wang J, Li L, Liu S, Zhao Y, Wang L and Du G: FOXC1 promotes melanoma by activating MST1R/PI3K/AKT. Oncotarget. 7:84375–84387. 2016.PubMed/NCBI
20	Zhu X, Wei L, Bai Y, Wu S and Han S: FoxC1 promotes epithelial-mesenchymal transition through PBX1 dependent transactivation of ZEB2 in esophageal cancer. Am J Cancer Res. 7:1642–1653. 2017.PubMed/NCBI
21	Huang L, Huang Z, Fan Y, He L, Ye M, Shi K, Ji B, Huang J, Wang Y and Li Q: FOXC1 promotes proliferation and epithelial-mesenchymal transition in cervical carcinoma through the PI3K-AKT signal pathway. Am J Transl Res. 9:1297–1306. 2017.PubMed/NCBI
22	Liu Y, Han L, Bai Y, Du W and Yang B: Down-regulation of MicroRNA-133 predicts poor overall survival and regulates the growth and invasive abilities in glioma. Artif Cells Nanomed Biotechnol. 46:206–210. 2018. View Article : Google Scholar : PubMed/NCBI
23	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
24	Yu H, Xue Y, Wang P, Liu X, Ma J, Zheng J, Li Z, Cai H and Liu Y: Knockdown of long non-coding RNA XIST increases blood-tumor barrier permeability and inhibits glioma angiogenesis by targeting miR-137. Oncogenesis. 6:e3032017. View Article : Google Scholar : PubMed/NCBI
25	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 Rep. 17:4392–4398. 2018.PubMed/NCBI
26	Xu YY, Tian J, Hao Q and Yin LR: MicroRNA-495 downregulates FOXC1 expression to suppress cell growth and migration in endometrial cancer. Tumour Biol. 37:239–251. 2016. View Article : Google Scholar : PubMed/NCBI
27	Deng L, Liu T, Zhang B, Wu H, Zhao J and Chen J: Forkhead box C1 is targeted by microRNA-133b and promotes cell proliferation and migration in osteosarcoma. Exp Ther Med. 14:2823–2830. 2017. View Article : Google Scholar : PubMed/NCBI
28	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
29	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
30	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
31	Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI
32	Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A and Lee E: The way Wnt works: Components and mechanism. Growth Factors. 31:1–31. 2013. View Article : Google Scholar : PubMed/NCBI
33	Anastas JN and Moon RT: WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 13:11–26. 2013. View Article : Google Scholar : PubMed/NCBI
34	Li Y, Zhu G, Zeng W, Wang J, Li Z, Wang B, Tian B, Lu D, Zhang X, Gao G and Li L: Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/β-catenin signaling through downregulating SOX7. Oncotarget. 8:65577–65587. 2017.PubMed/NCBI
35	Liu X, Wang L, Zhao S, Ji X, Luo Y and Ling F: β-catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastma cells. Med Oncol. 28:608–614. 2011. View Article : Google Scholar : PubMed/NCBI
36	Zhang K, Zhang J, Han L, Pu P and Kang C: Wnt/beta-catenin signaling in glioma. J Neuroimmune Pharmacol. 7:740–749. 2012. View Article : Google Scholar : PubMed/NCBI
37	Mishra S, Choe Y, Pleasure SJ and Siegenthaler JA: Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges. Dev Biol. 420:148–165. 2016. View Article : Google Scholar : PubMed/NCBI
38	Savage J, Voronova A, Mehta V, Sendi-Mukasa F and Skerjanc IS: Canonical Wnt signaling regulates Foxc1/2 expression in P19 cells. Differentiation. 79:31–40. 2010. View Article : Google Scholar : PubMed/NCBI