Bioinformatics analysis of the target gene of fibroblast growth factor receptor 3 in bladder cancer and associated molecular mechanisms

Ai,Xing; Jia,Zhuo‑Min; Wang,Juan; Di,Gui‑Ping; Zhang,Xu; Sun,Fengling; Zang,Tong; Liao,Xiumei

doi:10.3892/ol.2015.3231

July-2015 Volume 10 Issue 1

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July-2015 Volume 10 Issue 1

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Article

Bioinformatics analysis of the target gene of fibroblast growth factor receptor 3 in bladder cancer and associated molecular mechanisms

Authors:
- Xing Ai
- Zhuo‑Min Jia
- Juan Wang
- Gui‑Ping Di
- Xu Zhang
- Fengling Sun
- Tong Zang
- Xiumei Liao
View Affiliations / Copyright

Affiliations: Department of Urology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China, Department of Medicine, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China, Department of Urology, Chinese PLA General Hospital, Beijing 100853, P.R. China
Pages: 543-549
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Published online on: May 19, 2015

https://doi.org/10.3892/ol.2015.3231
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Abstract

The aim of the present study was to elucidate the molecular mechanisms of fibroblast growth factor receptor 3 (FGFR3) activation via overexpression or mutation of the FGFR3 target gene in bladder cancer (BC). The transcription profile data GSE41035, which included 18 BC samples, containing 3 independent FGFR3 short hairpin (sh)RNA, and 6 control samples, containing enhanced green fluorescent protein (EGFP) shRNA, were obtained from the National Center of Biotechnology Information Gene Expression Omnibus database. The Limma package with multiple testing correction was used to identify differentially expressed genes (DEGs) between FGFR3 knockdown and control samples. Gene ontology (GO) and pathway enrichment analysis were conducted in order to investigate the DEGs at the functional level. In addition, differential co‑expression analysis was employed to construct a gene co‑expression network. A total of 196 DEGs were acquired, of which 101 were downregulated and 95 were upregulated. In addition, a gene signature was identified linking FGFR3 signaling with de novo sterol biosynthesis and metabolism using GO and pathway enrichment analysis. Furthermore, the present study demonstrated that the genes NME2, CCNB1 and H2AFZ were significantly associated with BC, as determined by the protein‑protein interaction network of DEGs and co‑expressed genes. In conclusion, the present study revealed the involvement of FGFR3 in the regulation of sterol biosynthesis and metabolism in the maintenance of BC; in addition, the present study provided a novel insight into the molecular mechanisms of FGFR3 in BC. These results may therefore contribute to the theoretical guidance into the detection and therapy of BC.

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1	Bryan RT: Update on bladder cancer diagnosis and management. Trends in Urology and Men's Health. 4:7–11. 2013.
2	Ploeg M, Aben KK and Kiemeney LA: The present and future burden of urinary bladder cancer in the world. World J Urol. 27:289–293. 2009. View Article : Google Scholar : PubMed/NCBI
3	Billerey C, Chopin D, Aubriot-Lorton MH, et al: Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 158:1955–1959. 2001. View Article : Google Scholar : PubMed/NCBI
4	Heney NM: Natural history of superficial bladder cancer. Prognostic features and long-term disease course. Urol Clin North Am. 19:429–433. 1992.PubMed/NCBI
5	Parkin DM: The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl. 218:12–20. 2008. View Article : Google Scholar : PubMed/NCBI
6	Boffetta P: Tobacco smoking and risk of bladder cancer. Scand J Urol Nephrol Suppl. 218:45–54. 2008. View Article : Google Scholar : PubMed/NCBI
7	Zeegers MP, Tan FE, Dorant E and van Den Brandt PA: The impact of characteristics of cigarette smoking on urinary tract cancer risk: A meta-analysis of epidemiologic studies. Cancer. 89:630–639. 2000. View Article : Google Scholar : PubMed/NCBI
8	Sánchez-Carbayo M and Cordon-Cardó C: Molecular alterations associated with bladder cancer progression. Semin Oncol. 34:75–84. 2007. View Article : Google Scholar : PubMed/NCBI
9	Cordon-Cardo C: Molecular alterations associated with bladder cancer initiation and progression. Scand J Urol Nephrol Suppl. 218:154–165. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ornitz DM, Xu J, Colvin JS, et al: Receptor specificity of the fibroblast growth factor family. J Biol Chem. 271:15292–15297. 1996. View Article : Google Scholar : PubMed/NCBI
11	Thompson LM, Plummer S, Schalling M, et al: A gene encoding a fibroblast growth factor receptor isolated from the Huntington disease gene region of human chromosome 4. Genomics. 11:1133–1142. 1991. View Article : Google Scholar : PubMed/NCBI
12	Perez-Castro AV, Wilson J and Altherr MR: Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Fgfr3 Gene. Genomics. 41:10–16. 1997. View Article : Google Scholar : PubMed/NCBI
13	Pandith AA, Shah ZA and Siddiqi MA: Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urol Oncol. 31:398–406. 2013. View Article : Google Scholar : PubMed/NCBI
14	Turner N and Grose R: Fibroblast growth factor signalling: From development to cancer. Nat Rev Cancer. 10:116–129. 2010. View Article : Google Scholar : PubMed/NCBI
15	Passos-Bueno MR, Wilcox WR, Jabs EW, Sertié AL, Alonso LG and Kitoh H: Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 14:115–125. 1999. View Article : Google Scholar : PubMed/NCBI
16	Hernández S, de Muga S, Agell L, et al: FGFR3 mutations in prostate cancer: association with low-grade tumors. Mod Pathol. 22:848–856. 2009.PubMed/NCBI
17	Rosty C, Aubriot MH, Cappellen D, et al: Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Mol Cancer. 4:152005. View Article : Google Scholar : PubMed/NCBI
18	Cappellen D, De Oliveira C, Ricol D, et al: Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 23:18–20. 1999. View Article : Google Scholar : PubMed/NCBI
19	Billerey C, Chopin D, Aubriot-Lorton MH, et al: Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 158:1955–1959. 2001. View Article : Google Scholar : PubMed/NCBI
20	Jebar AH, Hurst CD, Tomlinson DC, Johnston C, Taylor CF and Knowles MA: FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene. 24:5218–5225. 2005. View Article : Google Scholar : PubMed/NCBI
21	Du X, Wang QR, Chan E, et al: FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. Cancer Res. 72:5843–5855. 2012. View Article : Google Scholar : PubMed/NCBI
22	Tomlinson DC, Hurst CD and Knowles MA: Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 26:5889–5899. 2007. View Article : Google Scholar : PubMed/NCBI
23	Miyake M, Ishii M, Koyama N, et al: 1-tert-butyl-3-[6-(3, 5-dimethoxy-phenyl)-2-(4-diethylamino-butylamino)-pyrido [2, 3-d] pyrimidin-7-yl]-urea (PD173074), a selective tyrosine kinase inhibitor of fibroblast growth factor receptor-3 (FGFR3), inhibits cell proliferation of bladder cancer carrying the FGFR3 gene mutation along with up-regulation of p27 Kip1 and G1 G0 arrest. J Pharmacol Exp Ther. 332:795–802. 2010. View Article : Google Scholar : PubMed/NCBI
24	Irizarry RA, Hobbs B, Collin F, et al: Exploration, normalization and summaries of high density oligonucleotide array probe level data. Biostatistics. 4:249–264. 2003. View Article : Google Scholar : PubMed/NCBI
25	Smyth GK: Limma: linear models for microarray dataBioinformatics and Computational Biology Solutions Using R and Bioconductor. Gentleman R, Carey V, Huber W, Irizarry RA and Dudoit S: Springer; New York, NY: pp. 397–420. 2005
26	Benjamini Y and Hochberg Y: Controlling the false discovery rate: A practical and powerful approach to multiple testing. J Roy Statist Soc Ser B (Methodological). 57:289–300. 1995.
27	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
28	Cowley MJ, Pinese M, Kassahn KS, et al: PINA v2.0: Mining interactome modules. Nucleic Acids Res. 40:(Database Issue). D862–D865. 2012. View Article : Google Scholar : PubMed/NCBI
29	Shannon P, Markiel A, Ozier O, et al: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
30	Jansen R, Greenbaum D and Gerstein M: Relating whole-genome expression data with protein-protein interactions. Genome Res. 12:37–46. 2002. View Article : Google Scholar : PubMed/NCBI
31	Kemmeren P, van Berkum NL, Vilo J, et al: Protein interaction verification and functional annotation by integrated analysis of genome-scale data. Mol Cell. 9:1133–1143. 2002. View Article : Google Scholar : PubMed/NCBI
32	Liu BH, Yu H, Tu K, Li C, Li YX and Li YY: DCGL: An R package for identifying differentially coexpressed genes and links from gene expression microarray data. Bioinformatics. 26:2637–2638. 2010. View Article : Google Scholar : PubMed/NCBI
33	Yokoyama C, Wang X, Briggs MR, et al: SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 75:187–197. 1993. View Article : Google Scholar : PubMed/NCBI
34	Porstmann T, Griffiths B, Chung YL, et al: PKB Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 24:6465–6481. 2005.PubMed/NCBI
35	Wu J, Liu J, Jia R and Song H: Nur77 inhibits androgen-induced bladder cancer growth. Cancer Invest. 31:654–660. 2013. View Article : Google Scholar : PubMed/NCBI
36	Degener S, Roth S, Mathers MJ and Ubrig B: Follow-up care-consequences of urinary diversion after bladder cancer. Urologe A. 53:253–262. 2014.(In German). View Article : Google Scholar : PubMed/NCBI
37	Lascu I: The nucleoside diphosphate kinases 1973–2000. J Bioenerg Biomembr. 32:211–214. 2000. View Article : Google Scholar
38	Rayner K, Chen YX, Hibbert B, et al: Discovery of NM23-H2 as an estrogen receptor β-associated protein: Role in estrogen-induced gene transcription and cell migration. J Steroid Biochem Mol Biol. 108:72–81. 2008. View Article : Google Scholar : PubMed/NCBI
39	Steeg PS, Bevilacqua G, Kopper L, et al: Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 80:200–204. 1988. View Article : Google Scholar : PubMed/NCBI
40	Yong G: Expression of C-erbB-2, EGFR and nm23-H1 in human bladder cancer and its clinical significance. Proc Clin Med. 2011((5)): 333–365. 2011.
41	Cook LM, Hurst DR and Welch DR: Metastasis suppressors and the tumor microenvironment. Semin Cancer Biol. 21:113–122. 2011. View Article : Google Scholar : PubMed/NCBI
42	Legin AA, Jakupec MA, Bokach NA, Tyan MR, Kukushkin VY and Keppler BK: Guanidine platinum (II) complexes: Synthesis, in vitro antitumor activity and DNA interactions. J Inorg Biochem. 133:33–39. 2014. View Article : Google Scholar : PubMed/NCBI
43	Chen S, Su L, Qiu J, et al: Mechanistic studies for the role of cellular nucleic-acid-binding protein (CNBP) in regulation of c-myc transcription. Biochim Biophys Acta. 1830:4769–4777. 2013. View Article : Google Scholar : PubMed/NCBI
44	Poli A, Ramazzotti G, Matteucci A, et al: A novel DAG-dependent mechanism links PKCα and Cyclin B1 regulating cell cycle progression. Oncotarget. 30:11526–11540. 2014.
45	Soria JC, Jang SJ, Khuri FR, et al: Overexpression of cyclin B1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res. 60:4000–4004. 2000.PubMed/NCBI
46	Nakamura N, Yamamoto H, Yao T, et al: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol. 36:828–837. 2005. View Article : Google Scholar : PubMed/NCBI
47	Yuan J, Krämer A, Matthess Y, et al: Stable gene silencing of cyclin B1 in tumor cells increases susceptibility to taxol and leads to growth arrest in vivo. Oncogene. 25:1753–1762. 2006. View Article : Google Scholar : PubMed/NCBI
48	Xu Y, Ayrapetov MK, Xu C, et al: Histone H2A.Z controls a critical chromatin remodeling step required for DNA double-strand break repair. Mol Cell. 48:723–733. 2012. View Article : Google Scholar : PubMed/NCBI
49	Meneghini MD, Wu M and Madhani HD: Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell. 112:725–736. 2003. View Article : Google Scholar : PubMed/NCBI
50	Dong L, Bard AJ, Richards WG, Nitz MD, Theodorescu D, Bueno R and Gordon GJ: A gene expression ratio-based diagnostic test for bladder cancer. Adv Appl Bioinform Chem. 2:17–22. 2009.PubMed/NCBI