Acta Biochimica et Biophysica Sinica Advance Access originally published online on April 8, 2009
Acta Biochimica et Biophysica Sinica 2009 41(5):414-428; doi:10.1093/abbs/gmp025
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Identification of aberrant cell cycle regulation in Epstein–Barr virus-associated nasopharyngeal carcinoma by cDNA microarray and gene set enrichment analysis
1 Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China
2 Department of Pathology, Second Xiangya Hospital, Central South University, Changsha 410011, China
3 Xiangya Hospital, Central South University, Changsha 410078, China
4 Third Xiangya Hospital, Central South University, Changsha 410013, China
5 Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha 410013, China
* Corresponding address. Tel: +86-731-4805383; E-mail: ligy{at}xysm.net
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Abstract |
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Previous studies have revealed that Epstein–Barr virus (EBV) was closely associated with nasopharyngeal carcinoma (NPC). This study aimed to characterize the global pathways affected in the EBV-associated NPC. Combined with microdissection, gene expression profiles in 22 NPCs and 10 non-tumor nasopharyngeal epithelial (NPE) tissue samples were analyzed. All NPC specimens served in the microarray analysis were positive for EBV, as judged by identification of the expression of EBV nuclear antigen 1 (EBNA1). Through gene set enrichment analysis (GSEA), we found that cell cycle pathway was the most disregulated pathway in NPC (P = 0.000, false discovery rate q-value = 0.007), which included some aberrant expressed components. We first found that overexpression of CDK4, cyclin D1, and Rb proteins, and loss of expression of proteins p16, p27, and p19 were statistically significant in NPC tissues compared with non-cancerous NPE (P < 0.05) by real-time RT–PCR and tissue microarray. EBV-encoded small RNA-1 (EBER-1) hybridization signals in the NPC showed significant associations with the overexpression of Rb (P = 0.000), cyclin D1 (P = 0.000), CDK4 (P = 0.000), and the loss of expression of p16 proteins (P = 0.039). In the final logistic regression analysis model, EBER-1 and abnormal expression of p16, Rb, cyclin D1, and E2F6 were independent contributions to nasopharyngeal carcinogenesis. Through survival analysis, only cyclin D1 could predict the prognosis of NPC patients. These results suggested that cell cycle pathway was the most disregulated pathway in the EBV-associated NPC, and EBER-1 was closely associated with p16, CDK4, cyclin D1, and Rb. cyclin D1 could be the prognosis biomarker for NPC.
Keywords signaling pathway; nasopharyngeal carcinoma; gene set enrichment analysis; cDNA microarray; tissue microarray; Epstein–Barr virus
Received: October 25, 2008; Accepted: January 22, 2009
These authors contributed equally to this work.