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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

Journal of Orthopaedic Surgery and Research 1/2015

Identification of genes associated with methotrexate resistance in methotrexate-resistant osteosarcoma cell lines

Journal of Orthopaedic Surgery and Research > Ausgabe 1/2015
Xiao-rong Yang, Yan Xiong, Hong Duan, Ren-rong Gong
Wichtige Hinweise
Xiao-rong Yang and Yan Xiong are first authors.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

XY and YX participated in the design of this study, and they both performed the statistical analysis. HD carried out the study and collected important background information. RG drafted the manuscript. All authors read and approved the final manuscript.



This study aimed to better understand the mechanisms underlying methotrexate (MTX)—resistance in osteosarcoma.


The raw transcription microarray data GSE16089 collected from three MTX-sensitive osteosarcoma (Saos-2) cell samples and three MTX-resistant osteosarcoma (Saos-2) cell samples were downloaded from Gene Expression Omnibus. After data processing, the differentially expressed genes (DEGs) were identified. Next, DEGs were submitted to DAVID for functional annotation based on the GO (Gene Ontology) database, as well as pathway enrichment analysis based on the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. Transcription factors (TFs) and tumor-associated genes (TAGs) were identified with reference to TRANSFAC and TAG, and TSGene databases, respectively. The protein-protein interaction (PPI) network of the gene-encoded products was constructed, and the subnetwork with the highest score was also detected using Search Tool for the Retrieval of Interacting Genes and BioNet package.


A total of 690 up-regulated genes and down-regulated 626 genes were identified. Up-regulated DEGs (including AARS and PARS2) were associated to transfer RNA (tRNA) aminoacylation while down-regulated DEGs (including AURKA, CCNB1, CCNE2, CDK1, and CENPA) were correlated with mitotic cell cycle. Totally, 13 TFs (including HMGB2), 13 oncogenes (including CCNA2 and AURKA), and 19 tumor suppressor genes (TSGs) (including CDKN2C) were identified from the down-regulated DEGs. Ten DEGs, including nine down-regulated genes (such as AURKA, CDK1, CCNE2, and CENPA) and one up-regulated gene (GADD45A), were involved in the highest score subnetwork.


AARS, AURKA, AURKB, CENPA, CCNB1, CCNE2, and CDK may contribute to MTX resistance via aminoacyl-tRNA biosynthesis pathway, cell cycle pathway, or p53 signaling pathway.
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Reviewer Acknowledgement

Reviewer acknowledgement 2014



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