Integrated analysis of gene expression and copy number variations in MET proto‑oncogene‑transformed human primary osteoblasts

Jia,Ru‑Jiang; Lan,Chun‑Gen; Wang,Xiu‑Chao; Gao,Chun‑Tao

doi:10.3892/mmr.2017.8135

Integrated analysis of gene expression and copy number variations in MET proto‑oncogene‑transformed human primary osteoblasts

Authors:
- Ru‑Jiang Jia
- Chun‑Gen Lan
- Xiu‑Chao Wang
- Chun‑Tao Gao
View Affiliations

Affiliations: Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
Published online on: November 22, 2017 https://doi.org/10.3892/mmr.2017.8135
Pages: 2543-2548

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

The aim of the present study was to screen the potential osteosarcoma (OS)‑associated genes and to obtain additional insight into the pathogenesis of OS. Transcriptional profile (ID: GSE28256) and copy number variations (CNV) profile were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MET proto‑oncogene‑transformed human primary osteoblast (MET‑HOB) samples and the control samples were identified using the Linear Models for Microarray Data package. Subsequently, CNV areas and CNVs were identified using cut‑off criterion of >30%‑overlap within the cases using detect_cnv.pl in PennCNV. Genes shared in DEGs and CNVs were obtained and discussed. Additionally, the Database for Annotation, Visualization and Integrated Discovery was used to identify significant Gene Ontology (GO) functions and pathways in DEGs with P<0.05. A total of 1,601 DEGs were screened out in MET‑HOBs and compared with control samples, including 784 upregulated genes, such as E2F transcription factor 1 (E2F1) and 2 (E2F2) and 817 downregulated genes, such as retinoblastoma 1 (RB1) and cyclin D1 (CCND1). DEGs were enriched in 344 GO terms, such as extracellular region part and extracellular matrix and 14 pathways, including pathways in cancer and extracellular matrix‑receptor interaction. Additionally, 239 duplications and 439 deletions in 678 genes from 1,313 chromosome regions were detected. A total of 12 genes were identified to be CNV‑driven genes, including cadherin 18, laminin subunit α 1, spectrin β, erythrocytic, ciliary rootlet coiled‑coil, rootletin pseudogene 2, β‑1,4-N-acetyl-galactosaminyltransferase 1, G protein regulated inducer of neurite outgrowth 1, EH domain binding protein 1‑like 1, growth factor independent 1, cathepsin Z, WNK lysine deficient protein kinase 1, glutathione S‑transferase mu 2 and microsomal glutathione S‑transferase 1. Therefore, cell cycle‑associated genes including E2F1, E2F2, RB1 and CCND1, and cell adhesion‑associated genes, such as CDH18 and LAMA1 may be used as diagnosis and/or therapeutic markers for patients with OS.

View Figures

View References

1	Heymann D and Rédini F: Targeted therapies for bone sarcomas. Bonekey Rep. 2:3782013. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
3	Li C, Cheng Q, Liu J, Wang B, Chen D and Liu Y: Potent growth-inhibitory effect of TRAIL therapy mediated by double-regulated oncolytic adenovirus on osteosarcoma. Mol Cell Biochem. 364:337–344. 2012. View Article : Google Scholar : PubMed/NCBI
4	He JP, Hao Y, Wang XL, Yang XJ, Shao JF, Guo FJ and Feng JX: Review of the molecular pathogenesis of osteosarcoma. Asian Pac J Cancer Prev. 15:5967–5976. 2014. View Article : Google Scholar : PubMed/NCBI
5	Xiong Y, Wu S, Du Q, Wang A and Wang Z: Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS). Cancer Gene Ther. 22:524–529. 2015. View Article : Google Scholar : PubMed/NCBI
6	Molyneux SD, Di Grappa MA, Beristain AG, McKee TD, Wai DH, Paderova J, Kashyap M, Hu P, Maiuri T, Narala SR, et al: Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J Clin Invest. 120:3310–3325. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tang N, Song WX, Luo J, Haydon RC and He TC: Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res. 466:2114–2130. 2008. View Article : Google Scholar : PubMed/NCBI
8	Walkley CR, Qudsi R, Sankaran VG, Perry JA, Gostissa M, Roth SI, Rodda SJ, Snay E, Dunning P, Fahey FH, et al: Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev. 22:1662–1676. 2008. View Article : Google Scholar : PubMed/NCBI
9	Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, Chambert KD, Davies G, Legge SE, Moran JL, et al: The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 75:378–385. 2014. View Article : Google Scholar : PubMed/NCBI
10	Riccardi VM and Lupski JR: Duplications, deletions, and single-nucleotide variations: The complexity of genetic arithmetic. Genet Med. 15:172–173. 2013. View Article : Google Scholar : PubMed/NCBI
11	Porat RM, Pasic I, Shlien A, Golgoz N, Andrulis I, Wunder JS and Malkin D: Genome-wide copy number analysis reveals two novel loci for susceptibility to sporadic osteosarcoma. Cancer Res. 71 8 Suppl:S53342011. View Article : Google Scholar
12	Luo Y, Deng Z and Chen J: Pivotal regulatory network and genes in osteosarcoma. Arch Med Sci. 9:569–575. 2013. View Article : Google Scholar : PubMed/NCBI
13	MacEwen EG, Kutzke J, Carew J, Pastor J, Schmidt JA, Tsan R, Thamm DH and Radinsky R: c-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells. Clin Exp Metastasis. 20:421–430. 2003. View Article : Google Scholar : PubMed/NCBI
14	Ferracini R, Angelini P, Cagliero E, Linari A, Martano M, Wunder J and Buracco P: MET oncogene aberrant expression in canine osteosarcoma. J Orthop Res. 18:253–256. 2000. View Article : Google Scholar : PubMed/NCBI
15	Coltella N, Manara MC, Cerisano V, Trusolino L, Di Renzo MF, Scotlandi K and Ferracini R: Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. FASEB J. 17:1162–1164. 2003.PubMed/NCBI
16	Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H and Tsuneyoshi M: Expression of c-met proto-oncogene product (c-MET) in benign and malignant bone tumors. Mod Pathol. 10:832–838. 1997.PubMed/NCBI
17	Dani N, Olivero M, Mareschi K, van Duist MM, Miretti S, Cuvertino S, Patanè S, Calogero R, Ferracini R, Scotlandi K, et al: The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors. J Bone Miner Res. 27:1322–1334. 2012. View Article : Google Scholar : PubMed/NCBI
18	Huang DW, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, Stephens R, Baseler MW, Lane HC and Lempicki RA: The DAVID gene functional classification tool: A novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 8:R1832007. View Article : Google Scholar : PubMed/NCBI
19	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
20	Mohseny AB, Tieken C, van der Velden PA, Szuhai K, de Andrea C, Hogendoorn PC and Cleton-Jansen AM: Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma. Genes Chromosomes Cancer. 49:1095–1103. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lim JH, Chang YC, Park YB, Park JW and Kwon TK: Transcriptional repression of E2F gene by proteasome inhibitors in human osteosarcoma cells. Biochem Biophys Res Commun. 318:868–872. 2004. View Article : Google Scholar : PubMed/NCBI
22	Tsantoulis PK and Gorgoulis VG: Involvement of E2F transcription factor family in cancer. Eur J Cancer. 41:2403–2414. 2005. View Article : Google Scholar : PubMed/NCBI
23	Helt AM and Galloway DA: Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis. 24:159–169. 2003. View Article : Google Scholar : PubMed/NCBI
24	Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N and Helin K: The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol. 13:7813–7825. 1993. View Article : Google Scholar : PubMed/NCBI
25	Nevins JR: The Rb/E2F pathway and cancer. Hum Mol Genet. 10:699–703. 2001. View Article : Google Scholar : PubMed/NCBI
26	Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI
27	Gokgoz N, Wunder JS and Andrulis IL: Genome-wide analysis of DNA copy number variations in osteosarcoma. Cancer Res. 72 8 Suppl:S50752012. View Article : Google Scholar
28	Lynn M, Wang Y, Slater J, Shah N, Conroy J, Ennis S, Morris T, Betts DR, Fletcher JA and O'Sullivan MJ: High-resolution genome-wide copy-number analyses identify localized copy-number alterations in Ewing sarcoma. Diagn Mol Pathol. 22:76–84. 2013. View Article : Google Scholar : PubMed/NCBI
29	Ottaviano L, Schaefer KL, Gajewski M, Huckenbeck W, Baldus S, Rogel U, Mackintosh C, de Alava E, Myklebost O, Kresse SH, et al: Molecular characterization of commonly used cell lines for bone tumor research: A trans-European EuroBoNet effort. Genes Chromosomes Cancer. 49:40–51. 2010. View Article : Google Scholar : PubMed/NCBI
30	Liu YZ, Pei YF, Liu JF, Yang F, Guo Y, Zhang L, Liu XG, Yan H, Wang L, Zhang YP, et al: Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males. PLoS One. 4:e68272009. View Article : Google Scholar : PubMed/NCBI
31	Freeman SS, Allen SW, Ganti R, Wu J, Ma J, Su X, Neale G, Dome JS, Daw NC and Khoury JD: Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors. Cancer. 113:1453–1461. 2008. View Article : Google Scholar : PubMed/NCBI
32	Berx G and Van Roy F: Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol. 1:a0031292009. View Article : Google Scholar : PubMed/NCBI
33	Goss KH and Groden J: Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol. 18:1967–1979. 2000. View Article : Google Scholar : PubMed/NCBI
34	Yagi T and Takeichi M: Cadherin superfamily genes: Functions, genomic organization, and neurologic diversity. Genes Dev. 14:1169–1180. 2000.PubMed/NCBI
35	Venkatachalam R, Verwiel ET, Kamping EJ, Hoenselaar E, Görgens H, Schackert HK, Van Krieken JH, Ligtenberg MJ, Hoogerbrugge N, van Kessel AG and Kuiper RP: Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients. Int J Cancer. 129:1635–1642. 2011. View Article : Google Scholar : PubMed/NCBI
36	Dziadek M: Role of laminin-nidogen complexes in basement membrane formation during embryonic development. Experientia. 51:901–913. 1995. View Article : Google Scholar : PubMed/NCBI
37	Kleinman HK, Cannon FB, Laurie GW, Hassell JR, Aumailley M, Terranova VP, Martin GR and DuBois-Dalcq M: Biological activities of laminin. J Cell Biochem. 27:317–325. 1985. View Article : Google Scholar : PubMed/NCBI
38	Li X, Kong X, Huo Q, Guo H, Yan S, Yuan C, Moran MS, Shao C and Yang Q: Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition. Cancer Sci. 102:1151–1157. 2011. View Article : Google Scholar : PubMed/NCBI
39	Zhu K, Dai Z, Pan Q, Wang Z, Yang GH, Yu L, Ding ZB, Shi GM, Ke AW, Yang XR, et al: Metadherin promotes hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 17:7294–7302. 2011. View Article : Google Scholar : PubMed/NCBI
40	Wei Y, Hu G and Kang Y: Metadherin as a link between metastasis and chemoresistance. Cell Cycle. 8:2132–2137. 2009. View Article : Google Scholar : PubMed/NCBI
41	Zhu L, Zhang P, Yang Y, Buford AS, Wang WL, Thomas DG and Hughes DP: Abstract A53: Metadherin functions as a laminin receptor that is essential for metastasis and is associated with poor survival in osteosarcoma. Cancer Res. 74 20 Suppl:A532014. View Article : Google Scholar