Upregulation of FoxP4 in HCC promotes migration and invasion through regulation of EMT

Zhang,Gang; Zhang,Guangye

doi:10.3892/ol.2019.10049

Upregulation of FoxP4 in HCC promotes migration and invasion through regulation of EMT

Authors:
- Gang Zhang
- Guangye Zhang
View Affiliations

Affiliations: Department of Liver Diseases, Rizhao Hospital of Traditional Chinese Medicine, Rizhao, Shandong 276800, P.R. China
Published online on: February 19, 2019 https://doi.org/10.3892/ol.2019.10049
Pages: 3944-3951

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies have indicated that FoxP1, FoxP2 and FoxP3 play important roles in hepatocellular carcinoma (HCC). However, the effect of FoxP4 in HCC requires further elucidation. The aim of the present study was to explore the roles of FoxP4 in HCC and further decipher the detailed mechanism. In present study, it was found that FoxP4, which is overexpressed in HCC tissues and cell lines, facilitated EMT in HCC cell lines through regulation of Slug. First, increased expression of FoxP4 was identified in 110 pairs of human HCC tumor and their adjacent normal tissues. In addition, the association between FoxP4 expression and clinicopathological features of HCC patients indicated that FoxP4 played vital roles in HCC development. Subsequently, gain‑ and loss‑of‑function experiments indicated that FoxP4 promoted cellular proliferation, migration as well invasion. In addition, EMT, a key mechanism during cancer metastasis, was regulated by FoxP4. Furthermore, ChIP and qChIP as well as luciferase reporter assays indicated that Slug, an EMT‑associated transcription factor, was transcriptionally regulated by FoxP4. In conclusion, FoxP4 functioned as a tumor promoter in HCC cells by transcriptionally regulating Slug, and the present study highlighted the potential effects of FoxP4 on the prognosis and treatment of HCC.

View Figures

View References

1	Waly Raphael S, Yangde Z and Yuxiang C: Hepatocellular carcinoma: Focus on different aspects of management. ISRN Oncol. 2012:4216732012.PubMed/NCBI
2	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
3	Bosch FX, Ribes J, Diaz M and Cleries R: Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 127:S5–S16. 2004. View Article : Google Scholar : PubMed/NCBI
4	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
5	Faivre S, Bouattour M and Raymond E: Novel molecular therapies in hepatocellular carcinoma. Liver Int. 31 Suppl:S151–S160. 2011. View Article : Google Scholar
6	Pan FC and Wright C: Pancreas organogenesis: From bud to plexus to gland. Dev Dyn. 240:530–565. 2011. View Article : Google Scholar : PubMed/NCBI
7	Wang X, Sun J, Cui M, Zhao F, Ge C, Chen T, Yao M and Li J: Downregulation of FOXP1 inhibits cell prolife ration in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest. Int J Mol Sci. 17:E15012016. View Article : Google Scholar : PubMed/NCBI
8	Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, Liu CG, Volinia S, Croce CM, Schmittgen TD, et al: Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res. 68:5049–5058. 2008. View Article : Google Scholar : PubMed/NCBI
9	Yan X, Zhou H and Zhang T, Xu P, Zhang S, Huang W, Yang L, Gu X, Ni R and Zhang T: Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumour Biol. 36:9611–9619. 2015. View Article : Google Scholar : PubMed/NCBI
10	Yu Z, Lin X, Tian M and Chang W: microRNA196b promotes cell migration and invasion by targeting FOXP2 in hepatocellular carcinoma. Oncol Rep. 39:731–738. 2018.PubMed/NCBI
11	Zhang Y, Zhang S, Wang X, Liu J, Yang L, He S, Chen L and Huang J: Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J Clini Pathol. 65:528–533. 2012. View Article : Google Scholar
12	Shi JY, Ma LJ, Zhang JW, Duan M, Ding ZB, Yang LX, Cao Y, Zhou J, Fan J, Zhang X, et al: FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-beta/Smad2/3 signaling pathway. BMC Cancer. 17:6482017. View Article : Google Scholar : PubMed/NCBI
13	Katoh M and Katoh M: Human FOX gene family (Review). IntJ Oncol. 25:1495–1500. 2004.
14	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
15	Lam EW, Brosens JJ, Gomes AR and Koo CY: Forkhead box proteins: Tuning forks for transcriptional harmony. Nat Rev Cancer. 13:482–495. 2013. View Article : Google Scholar : PubMed/NCBI
16	Barasch J: Genes and proteins involved in mesenchymal to epithelial transition. Curr Opin Nephrol Hypertens. 10:429–436. 2001. View Article : Google Scholar : PubMed/NCBI
17	Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 3:155–166. 2002. View Article : Google Scholar : PubMed/NCBI
18	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
19	Lu SQ, Qiu Y, Dai WJ and Zhang XY: FOXR2 promotes the proliferation, invasion, and epithelial-mesenchymal transition in human colorectal cancer cells. Oncol Res. 25:681–689. 2017. View Article : Google Scholar : PubMed/NCBI
20	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
21	Li J, Xia L, Zhou Z, Zuo Z, Xu C, Song H and Cai J: MiR-186-5p upregulation inhibits proliferation, metastasis and epithelial-to-mesenchymal transition of colorectal cancer cell by targeting ZEB1. Arch Biochem Biophys. 640:53–60. 2018. View Article : Google Scholar : PubMed/NCBI
22	Sun C, Tao Y, Gao Y, Xia Y, Liu Y, Wang G and Gu Y: F-box protein 11 promotes the growth and metastasis of gastric cancer via PI3K/AKT pathway-mediated EMT. Biomed Pharmacother. 98:416–423. 2018. View Article : Google Scholar : PubMed/NCBI
23	Liu L, Wu B, Cai H, Li D, Ma Y, Zhu X, Lv Z, Fan Y and Zhang X: Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/beta-catenin signaling. Exp Cell Res. 362:532–540. 2018. View Article : Google Scholar : PubMed/NCBI
24	Guan X: Cancer metastases: Challenges and opportunities. Acta Pharm Sin B. 5:402–418. 2015. View Article : Google Scholar : PubMed/NCBI
25	Bruix J, Gores GJ and Mazzaferro V: Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut. 63:844–855. 2014. View Article : Google Scholar : PubMed/NCBI
26	Nordenstedt H, White DL and El-Serag HB: The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 42 Suppl:S206–S214. 2010. View Article : Google Scholar : PubMed/NCBI
27	Yang JD, Harmsen WS, Slettedahl SW, Chaiteerakij R, Enders FT, Therneau TM, Orsini L, Kim WR and Roberts LR: Factors that affect risk for hepatocellular carcinoma and effects of surveillance. Clin Gastroenterol Hepatol. 9:617–623. 2011. View Article : Google Scholar : PubMed/NCBI
28	Meng FD, Wei JC, Qu K, Wang ZX, Wu QF, Tai MH, Liu HC, Zhang RY and Liu C: FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. World J Gastroenterol. 21:196–213. 2015. View Article : Google Scholar : PubMed/NCBI
29	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
30	Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P and Postigo A: ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 29:3490–3500. 2010. View Article : Google Scholar : PubMed/NCBI
31	Tam WL and Weinberg RA: The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Med. 19:1438–1449. 2013. View Article : Google Scholar : PubMed/NCBI
32	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