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Identification and Functional Analysis of Differentially Expressed Genes Related to Metastatic Osteosarcoma

  • Niu, Feng (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Zhao, Song (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Xu, Chang-Yan (Medical Record Department, the First Hospital of Jilin University) ;
  • Chen, Lin (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Ye, Long (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Bi, Gui-Bin (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Tian, Gang (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Gong, Ping (Department of Spine Surgery, the First Hospital of Jilin University) ;
  • Nie, Tian-Hong (Department of Spine Surgery, the First Hospital of Jilin University)
  • Published : 2015.01.22

Abstract

Background: To explore the molecular mechanisms of metastatic osteosarcoma (OS) by using the microarray expression profiles of metastatic and non-metastatic OS samples. Materials and Methods: The gene expression profile GSE37552 was downloaded from Gene Expression Omnibus database, including 2 human metastatic OS cell line models and 2 two non-metastatic OS cell line models. The differentially expressed genes (DEGs) were identified by Multtest package in R language. In addition, functional enrichment analysis of the DEGs was performed by WebGestalt, and the protein-protein interaction (PPI) networks were constructed by Hitpredict, then the signal pathways of the genes involved in the networks were performed by Kyoto Encyclopaedia of Genes and Genomes (KEGG) automatic annotation server (KAAS). Results: A total of 237 genes were classified as DEGs in metastatic OS. The most significant up- and down-regulated genes were A2M (alpha-2-macroglobulin) and BCAN (brevican). The DEGs were significantly related to the response to hormone stimulus, and the PPI network of A2M contained IL1B (interleukin), LRP1 (low-density lipoprotein receptor-related protein 1) and PDGF (platelet-derived growth factor). Furthermore, the MAPK signaling pathway and focal adhesion were significantly enriched. Conclusions: A2M and its interactive proteins, such as IL1B, LRP1 and PDGF may be candidate target molecules to monitor, diagnose and treat metastatic OS. The response to hormone stimulus, MAPK signaling pathway and focal adhesion may play important roles in metastatic OS.

References

  1. Bielack SS, Kempf-Bielack B, Delling G, et al (2002). Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol, 20, 776-90. https://doi.org/10.1200/JCO.20.3.776
  2. Blennow K, Ricksten A, Prince J, et al (2000). No association between the ${\alpha}2$-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression. J Neural Transm, 107, 1065-79. https://doi.org/10.1007/s007020070052
  3. Boucher P, Gotthardt M (2004). LRP and PDGF signaling: a pathway to atherosclerosis. Trends Cardiovasc Med, 14, 55-60. https://doi.org/10.1016/j.tcm.2003.12.001
  4. Broadhead ML, Clark J, Myers DE, et al (2011). The molecular pathogenesis of osteosarcoma: a review. Sarcoma, 2011,
  5. Carracedo A, Ma L, Teruya-Feldstein J, et al (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 118, 3065.
  6. Charity R, Foukas A, Deshmukh N, Grimer R (2006). Vascular endothelial growth factor expression in osteosarcoma. Clin Orthop Relat Res, 448, 193-8. https://doi.org/10.1097/01.blo.0000205877.05093.c9
  7. Diao C-Y, Guo HB, Ouyang YR, et al (2013). Screening for metastatic osteosarcoma biomarkers with a DNA microarray. Asian Pac J Cancer Prev, 15, 1817-22.
  8. Duncan D, Prodduturi N, Zhang B (2010). WebGestalt2: an updated and expanded version of the Web-based Gene Set Analysis Toolkit. BMC Bioinformatics, 11, 10. https://doi.org/10.1186/1471-2105-11-10
  9. Flores RJ, Li Y, Yu A, et al (2012). A systems biology approach reveals common metastatic pathways in osteosarcoma. BMC Syst Biol, 6, 50. https://doi.org/10.1186/1752-0509-6-50
  10. Fuchs B, Pritchard DJ (2002). Etiology of osteosarcoma. Clin Orthop Relat Res, 397, 40-52. https://doi.org/10.1097/00003086-200204000-00007
  11. Fujita A, Sato J, Rodrigues L, et al (2006). Evaluating different methods of microarray data normalization. BMC Bioinformatics, 7, 469. https://doi.org/10.1186/1471-2105-7-469
  12. Fujita T, Nagayama A, Anazawa S (2003). Circulating alpha-2-macroglobulin levels and depression scores in patients who underwent abdominal cancer surgery. J Surg Res, 114, 90-4. https://doi.org/10.1016/S0022-4804(03)00194-X
  13. He Y, Liang X, Meng C, et al (2014). Genetic polymorphisms of interleukin-1 beta and osteosarcoma risk. Int Orthop, 1-6.
  14. Herz J, Strickland D K (2001). LRP: a multifunctional scavenger and signaling receptor. J Clin Invest, 108, 779-84. https://doi.org/10.1172/JCI200113992
  15. Hu J, Feng D, Cheng R (2001). Expressions of p-MAPK, cyclin D1, p53 protein and their relationship in osteosarcoma. Hunan Yi Ke Da Xue Xue Bao, 26, 325.
  16. Hulka BS, Moorman PG (2008). Reprint of breast cancer: hormones and other risk factors. Maturitas, 61, 203-13. https://doi.org/10.1016/j.maturitas.2008.11.016
  17. Jia J, Tian Q, Liu Y, et al (2013). Interactive effect of bisphenol A (BPA) exposure with-22G/C polymorphism in LOX gene on the risk of osteosarcoma. Asian Pac J Cancer Prev, 14, 3805-8. https://doi.org/10.7314/APJCP.2013.14.6.3805
  18. Jiang W G, Ye L, Ji K, et al (2013). Antitumour effects of Yangzheng Xiaoji in human osteosarcoma: The pivotal role of focal adhesion kinase signalling. Oncol Rep, 30, 1405-13.
  19. Kansara M, Thomas DM (2007). Molecular pathogenesis of osteosarcoma. DNA Cell Biol, 26, 1-18. https://doi.org/10.1089/dna.2006.0505
  20. Kaste SC, Pratt CB, Cain AM, et al (1999). Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis. Cancer, 86, 1602-8. https://doi.org/10.1002/(SICI)1097-0142(19991015)86:8<1602::AID-CNCR31>3.0.CO;2-R
  21. Kubista B, Klinglmueller F, Bilban M, et al (2011). Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma. Int Orthop, 35, 401-11. https://doi.org/10.1007/s00264-010-0996-6
  22. Kubo T, Piperdi S, Rosenblum J, et al (2008). Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer, 112, 2119-29. https://doi.org/10.1002/cncr.23437
  23. Kulmambetova GN, Imanbekova MK, Logvinenko AA, et al (2014). Association of cytokine gene polymorphisms with gastritis in a kazakh population. Asian Pac J Cancer Prev, 15, 7763. https://doi.org/10.7314/APJCP.2014.15.18.7763
  24. Langlois B, Perrot G, Schneider C, et al (2010). LRP-1 promotes cancer cell invasion by supporting ERK and inhibiting JNK signaling pathways. PLoS One, 5, 11584. https://doi.org/10.1371/journal.pone.0011584
  25. Lee S-G, Kim B, Choi W, et al (2003). Lack of association between pro-inflammatory genotypes of the interleukin-1 (IL-1B-31 C/+ and IL-1RN* 2/* 2) and gastric cancer/duodenal ulcer in Korean population. Cytokine, 21, 167-71. https://doi.org/10.1016/S1043-4666(03)00032-2
  26. Li CJ, Cong Y, Liu XZ, et al (2014). Research progress on the livin gene and osteosarcomas. Asian Pac J Cancer Prev, 15, 8577-9. https://doi.org/10.7314/APJCP.2014.15.20.8577
  27. Lin DS, Cai LY, Ding J, Gao WY (2014). Correlation between E-cadherin-regulated cell adhesion and human osteosarcoma MG-63 cell anoikis. Asian Pac J Cancer Prev, 15, 8203-7. https://doi.org/10.7314/APJCP.2014.15.19.8203
  28. Linja MJ, Savinainen KJ, Saramaki O R, et al (2001). Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res, 61, 3550-5.
  29. Link MP, Goorin AM, Miser AW, et al (1986). The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med, 314, 1600. https://doi.org/10.1056/NEJM198606193142502
  30. Luo Y, Deng Z, Chen J (2013). Pivotal regulatory network and genes in osteosarcoma. Arch Med Sci, 9, 569-75.
  31. MacMahon B, Cole P, Brown J (1973). Etiology of human breast cancer: a review. J Natl Cancer Inst, 50, 21-42.
  32. Mialou V, Philip T, Kalifa C, et al (2005). Metastatic osteosarcoma at diagnosis. Cancer, 104, 1100-9. https://doi.org/10.1002/cncr.21263
  33. Patil A, Nakai K, Nakamura H (2011). HitPredict: a database of quality assessed protein-protein interactions in nine species. Nucleic Acids Res, 39, 744-9. https://doi.org/10.1093/nar/gkq834
  34. Patil A, Nakamura H (2005). Filtering high-throughput protein-protein interaction data using a combination of genomic features. BMC Bioinformatics, 6, 100. https://doi.org/10.1186/1471-2105-6-100
  35. Pezzi CM, Pollock RE, Evans HL, et al (1990). Preoperative chemotherapy for soft-tissue sarcomas of the extremities. Ann Surge, 211, 476. https://doi.org/10.1097/00000658-199004000-00015
  36. Pignochino Y, Dell'Aglio C, Basirico M, et al (2013). The combination of sorafenib and everolimus abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin Cancer Res, 19, 2117-31. https://doi.org/10.1158/1078-0432.CCR-12-2293
  37. Rehman A A, Ahsan H, Khan F H (2013). alpha-2-Macroglobulin: a physiological guardian. J Cell Physiol, 228, 1665-75. https://doi.org/10.1002/jcp.24266
  38. Smida J, Baumhoer D, Rosemann M, et al (2010). Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res, 16, 4256-67. https://doi.org/10.1158/1078-0432.CCR-10-0284
  39. Smyth G K (2005). Limma: linear models for microarray data. Bioinformatics and computational biology solutions using R and Bioconductor. Springer.
  40. Ta HT, Dass CR, Choong PF, Dunstan DE (2009). Osteosarcoma treatment: state of the art. Cancer Metastasis Rev, 28, 247-63. https://doi.org/10.1007/s10555-009-9186-7
  41. Takagi S, Takemoto A, Takami M, et al (2014). Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis. Cancer Sci, 105, 983-8. https://doi.org/10.1111/cas.12464
  42. Tingting R, Wei G, Changliang P, et al (2010). Arsenic trioxide inhibits osteosarcoma cell invasiveness via MAPK signaling pathway. Cancer Biology Therapy, 10, 251-7. https://doi.org/10.4161/cbt.10.3.12349
  43. Trougakos IP, Chondrogianni N, Amarantos I, et al (2010). Genome-wide transcriptome profile of the human osteosarcoma Sa OS and U-2 OS cell lines. Cancer Genet Cytogenet, 196, 109-18. https://doi.org/10.1016/j.cancergencyto.2009.09.012
  44. Troyanskaya O, Cantor M, Sherlock G, et al (2001). Missing value estimation methods for DNA microarrays. Bioinformatics, 17, 520-5. https://doi.org/10.1093/bioinformatics/17.6.520
  45. Wang J, Zu J, Xu G, et al (2014). Inhibition of focal adhesion kinase induces apoptosis in human osteosarcoma SAOS-2 cells. Tumor Biol, 35, 1551-6. https://doi.org/10.1007/s13277-013-1214-0
  46. Yang R, Piperdi S, Gorlick R (2008). Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clin Cancer Res, 14, 6396-404. https://doi.org/10.1158/1078-0432.CCR-07-5113
  47. Ye J, Fang L, Zheng H, et al (2006). WEGO: a web tool for plotting GO annotations. Nucleic Acids Res, 34, 293-7. https://doi.org/10.1093/nar/gkl031
  48. Zhang B, Kirov S, Snoddy J (2005). WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res, 33, 741-8. https://doi.org/10.1093/nar/gki475

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