Receptor FGFRL1 acts as a tumor suppressor in nude mice when overexpressed in HEK 293 Tet-On cells

Zhuang,Lei; Steinberg,Florian; Trueb,Beat

doi:10.3892/ol.2016.5245

Receptor FGFRL1 acts as a tumor suppressor in nude mice when overexpressed in HEK 293 Tet-On cells

Authors:
- Lei Zhuang
- Florian Steinberg
- Beat Trueb
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Affiliations: Department of Clinical Research, University of Bern, CH‑3008 Bern, Switzerland
Published online on: October 12, 2016 https://doi.org/10.3892/ol.2016.5245
Pages: 4524-4530
Copyright: © Zhuang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fibroblast growth factor receptor-like 1 (FGFRL1) is a transmembrane receptor that interacts with heparin and FGF ligands. In contrast to the classical FGF receptors, FGFR1 to FGFR4, it does not appear to affect cell growth and proliferation. In the present study, an inducible gene expression system was utilized in combination with a xenograft tumor model to investigate the effects of FGFRL1 on cell adhesion and tumor formation. It was determined that recombinant FGFRL1 promotes the adhesion of HEK 293 Tet‑On® cells in vitro. Moreover, when such cells are induced to express FGFRL1ΔC they aggregate into huge clusters. If injected into nude mice, the cells form large tumors. Notably, this tumor growth is completely inhibited when the expression of FGFRL1 is induced. The forced expression of FGFRL1 in the tumor tissue may restore contact inhibition, thereby preventing growth of the cells in nude mice. The results of the present study demonstrate that FGFRL1 acts as a tumor suppressor similar to numerous other cell adhesion proteins. It is therefore likely that FGFRL1 functions as a regular cell‑cell adhesion protein.

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1	Kreis T and Vale R: Guidebook to the Extracellular MatrixAnchor and Adhesion Proteins. 2nd. Oxford University Press; 1999
2	Okegawa T, Li Y, Pong RC and Hsieh JT: Cell adhesion proteins as tumor suppressors. J Urol. 167:1836–1843. 2002. View Article : Google Scholar : PubMed/NCBI
3	Moh MC and Shen S: The roles of cell adhesion molecules in tumor suppression and cell migration: A new paradox. Cell Adh Migr. 3:334–336. 2009. View Article : Google Scholar : PubMed/NCBI
4	Pećina-Slaus N: Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int. 3:172003. View Article : Google Scholar : PubMed/NCBI
5	Ren B, Yu YP, Tseng GC, Wu C, Chen K, Rao UN, Nelson J, Michalopoulos GK and Luo JH: Analysis of integrin alpha7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma. J Natl Cancer Inst. 99:868–880. 2007. View Article : Google Scholar : PubMed/NCBI
6	Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM, Kandioler D, Berger W, Stiglbauer W, Depisch D, et al: Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 103:283–291. 2007. View Article : Google Scholar : PubMed/NCBI
7	Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, Murakami Y and Imamura M: Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res. 63:6320–6326. 2003.PubMed/NCBI
8	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
9	Trueb B: Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 68:951–964. 2010. View Article : Google Scholar : PubMed/NCBI
10	Trueb B, Zhuang L, Taeschler S and Wiedemann M: Characterization of FGFRL1, a novel fibroblast growth factor (FGF) receptor preferentially expressed in skeletal tissues. J Biol Chem. 278:33857–33865. 2003. View Article : Google Scholar : PubMed/NCBI
11	Ornitz DM and Itoh N: The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 4:215–266. 2015. View Article : Google Scholar : PubMed/NCBI
12	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
13	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
14	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
15	Rieckmann T, Kotevic I and Trueb B: The cell surface receptor FGFRL1 forms constitutive dimers that promote cell adhesion. Exp Cell Res. 314:1071–1081. 2008. View Article : Google Scholar : PubMed/NCBI
16	Steinberg F, Gerber SD, Rieckmann T and Trueb B: Rapid fusion and syncytium formation of heterologous cells upon expression of the FGFRL1 receptor. J Biol Chem. 285:37704–37715. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yang X, Steinberg F, Zhuang L, Bessey R and Trueb B: Receptor FGFRL1 does not promote cell proliferation but induces cell adhesion. Int J Mol Med. 38:30–38. 2016.PubMed/NCBI
18	Zhuang L, Gerber SD, Kuchen S, Villiger PM and Trueb B: Deletion of exon 8 from the EXT1 gene causes multiple osteochondromas (MO) in a family with three affected members. Springerplus. 5:712016. View Article : Google Scholar : PubMed/NCBI
19	Rieckmann T, Zhuang L, Flück CE and Trueb B: Characterization of the first FGFRL1 mutation identified in a craniosynostosis patient. Biochim Biophys Acta. 1792:112–121. 2009. View Article : Google Scholar : PubMed/NCBI
20	Henning A, Schneider M, Bur M, Blank F, Gehr P and Lehr CM: Embryonic chicken trachea as a new in vitro model for the investigation of mucociliary particle clearance in the airways. AAPS PharmSciTech. 9:521–527. 2008. View Article : Google Scholar : PubMed/NCBI
21	Zhuang L, Falquet L and Trueb B: Genome-wide comparison of FGFRL1 with structurally related surface receptors. Exp Ther Med. 1:161–168. 2010.PubMed/NCBI
22	Mandai K, Rikitake Y, Mori M and Takai Y: Nectins and nectin-like molecules in development and disease. Curr Top Dev Biol. 112:197–231. 2015. View Article : Google Scholar : PubMed/NCBI
23	Samanta D and Almo SC: Nectin family of cell-adhesion molecules: Structural and molecular aspects of function and specificity. Cell Mol Life Sci. 72:645–658. 2015. View Article : Google Scholar : PubMed/NCBI
24	Shen C, Gu M, Song C, Miao L, Hu L, Liang D and Zheng C: The tumorigenicity diversification in human embryonic kidney 293 cell line cultured in vitro. Biologicals. 36:263–268. 2008. View Article : Google Scholar : PubMed/NCBI
25	Tanaka T and Rabbitts TH: Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth. Oncogene. 29:6064–6070. 2010. View Article : Google Scholar : PubMed/NCBI
26	Schild C and Trueb: Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors. Int J Mol Med. 16:1169–1173. 2005.PubMed/NCBI
27	Barrett CL, DeBoever C, Jepsen K, Saenz CC, Carson DA and Frazer KA: Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy. Proc Natl Acad Sci USA. 112:E3050–E3057. 2015. View Article : Google Scholar : PubMed/NCBI
28	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
29	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
30	di Martino E, Taylor CF, Roulson JA and Knowles MA: An integrated genomic, transcriptional and protein investigation of FGFRL1 as a putative 4p16.3 deletion target in bladder cancer. Genes Chromosomes Cancer. 52:860–871. 2013. View Article : Google Scholar : PubMed/NCBI
31	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
32	Murakami S, Sakurai-Yageta M, Maruyama T and Murakami Y: Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg. PLoS One. 9:e1100622014. View Article : Google Scholar : PubMed/NCBI
33	Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT and Giaccia AJ: Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 35:856–867. 2009. View Article : Google Scholar : PubMed/NCBI