FGFRL1 deficiency reduces motility and tumorigenic potential of cells derived from oesophageal squamous cell carcinomas

Takei,Yoshinori; Matsumura,Takafumi; Watanabe,Kazuaki; Nakamine,Hirokazu; Sudo,Tetsuo; Shimizu,Kazuharu; Shimada,Yutaka

doi:10.3892/ol.2018.8739

FGFRL1 deficiency reduces motility and tumorigenic potential of cells derived from oesophageal squamous cell carcinomas

Authors:
- Yoshinori Takei
- Takafumi Matsumura
- Kazuaki Watanabe
- Hirokazu Nakamine
- Tetsuo Sudo
- Kazuharu Shimizu
- Yutaka Shimada
View Affiliations

Affiliations: Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606‑8501, Japan, Division of Pathology and Laboratory Medicine, The Japan Baptist Hospital, Kyoto 606‑8273, Japan
Published online on: May 18, 2018 https://doi.org/10.3892/ol.2018.8739
Pages: 809-814
Copyright: © Takei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Oesophageal squamous cell carcinoma (ESCC) is an aggressive cancer that resulted in ~400,000 mortalities worldwide in 2012. It was reported previously that fibroblast growth factor receptor‑like 1 (FGFRL1) is highly expressed in ESCC patients with lymph node metastasis and poor prognosis accordingly. FGFRL1 is an FGFR that lacks tyrosine kinase activity, whereas the activity is critical for other FGFRs to activate intracellular signalling. The mechanism by which FGFRL1 promotes the aggressiveness of ESCCs is unknown. In the present study, two independent FGFRL1‑deficient cell lines were generated from human ESCC KYSE520 cells, in order to investigate the relationship of FGFRL1 with the aggressiveness of ESCCs. FGFRL1‑deficiency did not affect proliferation of KYSE520 cells in vitro. However, a xenograft mouse model demonstrated that FGFRL1‑deficiency decelerated tumour growth in vivo. The haematoxylin‑eosin staining identified that FGFRL1‑deficient cells formed well‑differentiated squamous cell carcinomas, whereas wild‑type cells formed moderately differentiated squamous cell carcinomas. Microarray analysis of mRNA expression revealed that FGFRL1‑depletion resulted in decreased expression of proteins associated with motility and invasion of tumour cells, matrix metalloproteinase‑1 and fibroblast growth factor binding protein 1. The wound‑healing assay indicated that depleting FGFRL1 reduced cell motility. Furthermore, the invasiveness of FGFRL1‑deficient cells was lesser than that of wild‑type KYSE520 cells. In the FGFRL1‑deficient KYSE520 cells, actin filaments around the nucleus were observed sparsely, whereas the filaments along the plasma membranes were observed as frequently as those in the parent KYSE520 cells. These results demonstrate that FGFRL1 may be involved in regulation of protein expression, actin filament assembly and tumorigenic potential of ESCC cells.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E586. 2015. View Article : Google Scholar : PubMed/NCBI
2	Thrift AP: The epidemic of oesophageal carcinoma: Where are we now? Cancer Epidemiol. 41:88–95. 2016. View Article : Google Scholar : PubMed/NCBI
3	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
4	Tachimori Y, Ozawa S, Numasaki H, Ishihara R, Matsubara H, Muro K, Oyama T, Toh Y, Udagawa H, Uno T, et al: Comprehensive registry of esophageal cancer in Japan, 2010. Esophagus. 14:189–214. 2017. View Article : Google Scholar : PubMed/NCBI
5	Kuwano H, Nishimura Y, Oyama T, Kato H, Kitagawa Y, Kusano M, Shimada H, Takiuchi H, Toh Y, Doki Y, et al: Guidelines for diagnosis and treatment of carcinoma of the esophagus April 2012 edited by the Japan Esophageal Society. Esophagus. 12:1–30. 2015. View Article : Google Scholar : PubMed/NCBI
6	Wiedemann M and Trueb B: Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. Genomics. 69:275–279. 2000. View Article : Google Scholar : PubMed/NCBI
7	Stauber DJ, DiGabriele AD and Hendrickson WA: Structural interactions of fibroblast growth factor receptor with its ligands. Proc Natl Acad Sci USA. 97:49–54. 2000. View Article : Google Scholar : PubMed/NCBI
8	Trueb B: Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 68:951–964. 2011. View Article : Google Scholar : PubMed/NCBI
9	Gerber SD, Steinberg F, Beyeler M, Villiger PM and Trueb B: The murine Fgfrl1 receptor is essential for the development of the metanephric kidney. Dev Biol. 335:106–119. 2009. View Article : Google Scholar : PubMed/NCBI
10	Gerber SD, Amann R, Wyder S and Trueb B: Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling. PLoS One. 7:e334572012. View Article : Google Scholar : PubMed/NCBI
11	Baertschi S, Zhuang L and Trueb B: Mice with a targeted disruption of the Fgfrl1 gene die at birth due to alterations in the diaphragm. FEBS J. 274:6241–6253. 2007. View Article : Google Scholar : PubMed/NCBI
12	Amann R, Wyder S, Slavotinek AM and Trueb B: The FgfrL1 receptor is required for development of slow muscle fibers. Dev Biol. 394:228–241. 2014. View Article : Google Scholar : PubMed/NCBI
13	Tsuchiya S, Fujiwara T, Sato F, Shimada Y, Tanaka E, Sakai Y, Shimizu K and Tsujimoto G: MicroRNA-210 regulates cancer cell proliferation through targeting fibroblast growth factor receptor-like 1 (FGFRL1). J Biol Chem. 286:420–428. 2011. View Article : Google Scholar : PubMed/NCBI
14	Shimada Y, Okumura T, Nagata T, Hashimoto I, Sawada S, Yoshida T, Fukuoka J, Shimizu K and Tsukada K: Expression analysis of fibroblast growth factor receptor-like 1 (FGFRL1) in esophageal squamous cell carcinoma. Esophagus. 11:48–53. 2014. View Article : Google Scholar
15	Shimada Y, Okumura T, Takei Y, Watanabe K, Nagata T, Hori T, Tsuchiya S, Tsukada K and Shimizu K: Role of fibroblast growth factor receptors in esophageal squamous cell carcinoma. Esophagus. 13:30–41. 2016. View Article : Google Scholar
16	Zuo J, Wen M, Lei M, Peng X, Yang X and Liu Z: MiR-210 links hypoxia with cell proliferation regulation in human Laryngocarcinoma cancer. J Cell Biochem. 116:1039–1049. 2015. View Article : Google Scholar : PubMed/NCBI
17	Schild C and Trueb B: Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors. Int J Mol Med. 16:1169–1173. 2005.PubMed/NCBI
18	Donnard E, Asprino PF, Correa BR, Bettoni F, Koyama FC, Navarro FC, Perez RO, Mariadason J, Sieber OM, Strausberg RL, et al: Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy. Oncotarget. 5:9199–9213. 2014. View Article : Google Scholar : PubMed/NCBI
19	Shimada Y, Imamura M, Wagata T, Yamaguchi N and Tobe T: Characterization of 21 newly established esophageal cancer cell lines. Cancer. 69:277–284. 1992. View Article : Google Scholar : PubMed/NCBI
20	Pulukuri SM and Rao JS: Matrix metalloproteinase-1 promotes prostate tumor growth and metastasis. Int J Oncol. 32:757–765. 2008.PubMed/NCBI
21	Tassi E, McDonnell K, Gibby KA, Tilan JU, Kim SE, Kodack DP, Schmidt MO, Sharif GM, Wilcox CS, Welch WJ, et al: Impact of fibroblast growth factor-binding protein-1 expression on angiogenesis and wound healing. Am J Pathol. 179:2220–2232. 2011. View Article : Google Scholar : PubMed/NCBI
22	Bugyi B and Carlier MF: Control of actin filament treadmilling in cell motility. Annu Rev Biophys. 39:449–470. 2010. View Article : Google Scholar : PubMed/NCBI
23	Abuharbeid S, Czubayko F and Aigner A: The fibroblast growth factor-binding protein FGF-BP. Int J Biochem Cell Biol. 38:1463–1468. 2006. View Article : Google Scholar : PubMed/NCBI
24	Yamashita K, Mori M, Kataoka A, Inoue H and Sugimachi K: The clinical significance of MMP-1 expression in oesophageal carcinoma. Br J Cancer. 84:276–282. 2001. View Article : Google Scholar : PubMed/NCBI