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Identification of Biomarkers for Diagnosis of Gastric Cancer by Bioinformatics

  • Wang, Da-Guang (Gastrointestinal surgery, the First Hospital of Jilin University) ;
  • Chen, Guang (Vascular surgery, the First Hospital of Jilin University) ;
  • Wen, Xiao-Yu (Hepatobiliary and pancreatic, the First Hospital of Jilin University) ;
  • Wang, Dan (Gastrointestinal Department of Internal Medicine, the First Hospital of Jilin University) ;
  • Cheng, Zhi-Hua (Vascular surgery, the First Hospital of Jilin University) ;
  • Sun, Si-Qiao (Vascular surgery, the First Hospital of Jilin University)
  • Published : 2015.03.09

Abstract

Background: We aimed to discover potential gene biomarkers for gastric cancer (GC) diagnosis. Materials and Methods: Genechips of 10 GC tissues and 10 gastric mucosa (GM, para-carcinoma tissue, normal control) tissues were generated using an exon array of Affymetrix containing 30,000 genes. The differentially expressed genes (DEGs) between GC tissues and normal control were identified by the Limma package and analyzed by hierarchical clustering analysis. Gene ontology (GO) and pathway enrichment analyses were performed for investigating the functions of DEGs. Receiver operating characteristics (ROC) analysis was performed to measure the effects of biomarker candidates for diagnosis of GC. Results: Totals of 896 up-regulated and 60 down-regulated DEGs were identified to be differentially expressed between GC samples and normal control. Hierarchical clustering analysis showed that DEGs were highly differentially expressed and most DEGs were up-regulated. The most significantly enriched GO-BP term was revealed to be mitotic cell cycle and the most significantly enriched pathway was cell cycle. The intersection analysis showed that most significant DEGs were cyclin B1 (CCNB1) and cyclin B2 (CCNB2). The sensitivities and specificities of CCNB1 and CCNB2 were both high (p<0.0001). Areas under the ROC curve for CCNB1 and CCNB2 were both greater than 0.9 (p<0.0001). Conclusions: CCNB1 and CCNB2, which were involved in cell cycle, played significant roles in the progression and development of GC and these genes may be potential biomarkers for diagnosis and prognosis of GC.

Keywords

Gastric cancer;differentially expressed genes;diagnosis;biomarkers

References

  1. Begnami MD, Fregnani JHT, Nonogaki S, et al (2010). Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication. Human pathol, 41, 1120-7. https://doi.org/10.1016/j.humpath.2010.01.007
  2. Bolstad BM, Irizarry RA, Astrand M, et al (2003). A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics, 19, 185-93. https://doi.org/10.1093/bioinformatics/19.2.185
  3. Bridges JR CC (1966). Hierarchical cluster analysis. Psychol Rep, 18, 851-4. https://doi.org/10.2466/pr0.1966.18.3.851
  4. Carpelan-Holmstrom M, Louhimo J, Stenman U-H, et al (2001). CEA, CA 19-9 and CA 72-4 improve the diagnostic accuracy in gastrointestinal cancers. Anticancer Res, 22, 2311-6.
  5. Chow JP, Siu WY, Fung TK, et al (2003). DNA damage during the spindle-assembly checkpoint degrades Cdc25A, inhibits cyclin-cdc2 complexes, and reverses cells to interphase. Mol Biol Cell, 14, 3989-4002. https://doi.org/10.1091/mbc.E03-03-0168
  6. Consortium GO (2004). The Gene Ontology (GO) database and informatics resource. Nucleic acids Res, 32, 258-61. https://doi.org/10.1093/nar/gkh036
  7. Da Wei Huang BTS, Lempicki RA (2008). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4, 44-57. https://doi.org/10.1038/nprot.2008.211
  8. Dennis Jr G, Sherman BT, Hosack DA, et al (2003). DAVID: database for annotation, visualization, and integrated discovery. Genome Biol, 4, 3. https://doi.org/10.1186/gb-2003-4-5-p3
  9. Fawcett T (2006). An introduction to ROC analysis. Pattern Recogn Lett, 27, 861-74. https://doi.org/10.1016/j.patrec.2005.10.010
  10. Ford HL, Pardee AB (1999). Cancer and the cell cycle. J Cellular Biochem, 75, 166-72. https://doi.org/10.1002/(SICI)1097-4644(1999)75:32+<166::AID-JCB20>3.0.CO;2-J
  11. Gallant P, Nigg E (1992). Cyclin B2 undergoes cell cycledependent nuclear translocation and, when expressed as a non-destructible mutant, causes mitotic arrest in HeLa cells. J Cell Biol, 117, 213-24. https://doi.org/10.1083/jcb.117.1.213
  12. Garcia AME, Alfaro A, Palma I, et al (2013). Expression of biomarkers in cervical intraepithelial neoplasia: Potential use screening. Mol Cancer Ther, 12, A46. https://doi.org/10.1158/1535-7163.TARG-13-A46
  13. Gonzalez CA, Sala N, Rokkas T (2013). Gastric cancer: epidemiologic aspects. Helicobacter, 18, 34-8. https://doi.org/10.1111/hel.12082
  14. Hofmann H-S, Hansen G, Burdach S, et al (2004). Discrimination of human lung neoplasm from normal lung by two target genes. Am J Resp Crit Care Med, 170, 516-9. https://doi.org/10.1164/rccm.200401-127OC
  15. Irizarry RA, Hobbs B, Collin F, et al (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics, 4, 249-64. https://doi.org/10.1093/biostatistics/4.2.249
  16. Kanehisa M, Goto S (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic acids Res, 28, 27-30. https://doi.org/10.1093/nar/28.1.27
  17. Kawamoto H, Koizumi H, Uchikoshi T (1997). Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses. Am J Pathol, 150, 15.
  18. Kim D-H (2007). Prognostic implications of cyclin B1, p34cdc2, p27Kip1 and p53 expression in gastric cancer. Yonsei Med J, 48, 694-700. https://doi.org/10.3349/ymj.2007.48.4.694
  19. Kim D, Lee H, Nam E, et al (2000). Reduced expression of the cell-cycle inhibitor p27Kip1 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology, 36, 245-51. https://doi.org/10.1046/j.1365-2559.2000.00842.x
  20. Kushner J, Bradley G, Young B, et al (1999). Aberrant expression of cyclin A and cyclin B1 proteins in oral carcinoma. J Oral Pathol Med, 28, 77-81.
  21. Leung WK, Wu M-s, Kakugawa Y, et al (2008). Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol, 9, 279-87. https://doi.org/10.1016/S1470-2045(08)70072-X
  22. Li X-K, Motwani M, Tong W, et al (2000). Huanglian, a Chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol Pharm, 58, 1287-93. https://doi.org/10.1124/mol.58.6.1287
  23. Lin J-P, Yang J-S, Lee J-H, et al (2006). Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line. World J Gastroenterol, 12, 21. https://doi.org/10.3748/wjg.v12.i1.21
  24. Liu H, Zhu L, Liu B, et al (2012). Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer. Cancer Lett, 316, 196-203. https://doi.org/10.1016/j.canlet.2011.10.034
  25. Liu R, Zhang C, Hu Z, et al (2011). A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Euro J Cancer, 47, 784-91. https://doi.org/10.1016/j.ejca.2010.10.025
  26. Mashal RD, Lester S, Corless C, et al (1996). Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res, 56, 4159-63.
  27. Orditura M, Galizia G, Sforza V, et al (2014). Treatment of gastric cancer. World J Gastroenterol, 20, 1635-49. https://doi.org/10.3748/wjg.v20.i7.1635
  28. Otsubo T, Akiyama Y, Yanagihara K, et al (2008). SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Bri J Cancer, 98, 824-31. https://doi.org/10.1038/sj.bjc.6604193
  29. Park S-H, Yu G-R, Kim W-H, et al (2007). NF-Y-dependent cyclin B2 expression in colorectal adenocarcinoma. Clin Cancer Res, 13, 858-67. https://doi.org/10.1158/1078-0432.CCR-06-1461
  30. Sarafan-Vasseur N, Lamy A, Bourguignon J, et al (2002). Overexpression of B-type cyclins alters chromosomal segregation. Oncogene, 21, 2051-7. https://doi.org/10.1038/sj.onc.1205257
  31. Schwartz GK, Shah MA (2005). Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol, 23, 9408-21. https://doi.org/10.1200/JCO.2005.01.5594
  32. Smyth GK (2004). Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol.
  33. Suzuki H, Graziano DF, McKolanis J, et al (2005). T Cell dependent antibody responses against aberrantly expressed cyclin B1 protein in patients with cancer and premalignant disease. Clin Cancer Res, 11, 1521-6. https://doi.org/10.1158/1078-0432.CCR-04-0538
  34. Takahashi Y, Takeuchi T, Sakamoto J, et al (2003). The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study. Gastric Cancer, 6, 142-5. https://doi.org/10.1007/s10120-003-0240-9
  35. Takaishi S, Okumura T, Tu S, et al (2009). Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells, 27, 1006-20. https://doi.org/10.1002/stem.30
  36. Van Cutsem E, de Haas S, Kang Y-K, et al (2012). Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol, 39, 9824.
  37. Wang A, Yoshimi N, Ino N, et al (1997). Overexpression of cyclin B1 in human colorectal cancers. J Cancer Res Clin Oncol, 123, 124-7. https://doi.org/10.1007/BF01269891
  38. Yang L (2006). Incidence and mortality of gastric cancer in China. World J Gastroenterol, 12, 17-20. https://doi.org/10.3748/wjg.v12.i1.17
  39. Yasuda M, Takesue F, Inutsuka S, et al (2002). Overexpression of cyclin B1 in gastric cancer and its clinicopathological significance: an immunohistological study. J Cancer Res Clin Oncol, 128, 412-6. https://doi.org/10.1007/s00432-002-0359-9
  40. Yonemura Y, Ninomiya I, Yamaguchi A, et al (1991). Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res, 51, 1034-8.
  41. Yuan J, Kramer A, Matthess Y, et al (2005). Stable gene silencing of cyclin B1 in tumor cells increases susceptibility to taxol and leads to growth arrest in vivo. Oncogene, 25, 1753-62.
  42. Zhou X-Y, Wang X, Hu B, et al (2002). An ATM-independent S-phase checkpoint response involves CHK1 pathway. Cancer Res, 62, 1598-603.

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