Abstract
BackgroundThe purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance.MethodsWe used microarrays to compare the differences of both miRNA and mRNA expression profiles in the radioresistant NPC CNE2-IR and radiosensitive NPC CNE2 cells, applied qRT-PCR to confirm the reliability of microarray data, adopted databases prediction and anticorrelated analysis of miRNA and mRNA expression to identify the miRNA target genes, and employed bioinformatics tools to examine the functions and pathways in which miRNA target genes are involved, and construct a miRNA-target gene regulatory network. We further investigated the roles of miRNA-23a and its target gene IL-8 in the NPC radioresistance.ResultsThe main findings were fourfold: (1) fifteen differential miRNAs and 372 differential mRNAs were identified, and the reliability of microarray data was validated for randomly selected eight miRNAs and nine genes; (2) 174 miRNA target were identified, and most of their functions and regulating pathways were related to tumor therapeutic resistance; (3) a posttranscriptional regulatory network including 375 miRNA-target gene pairs was constructed, in which the ten genes were coregulated by the six miRNAs; (4) IL-8 was a direct target of miRNA-23a, the expression levels of IL-8 were elevated in the radioresistant NPC tissues and showed inverse correlation with miRNA-23a expression, and genetic upregulation of miRNA-23a and antibody neutralization of secretory IL-8 could reduce NPC cells radioresistance.ConclusionsWe identified fifteen differential miRNAs and 372 differential mRNAs in the radioresistant NPC cells, constructed a posttranscriptional regulatory network including 375 miRNA-target gene pairs, discovered the ten target genes coregulated by the six miRNAs, and validated that downregulated miRNA-23a was involved in NPC radioresistance through directly targeting IL-8. Our data form a basis for further investigating the mechanisms of NPC radioresistance.
Highlights
Nasopharyngeal carcinoma (NPC) is an endemic disease in southern China and Southeast Asia, and tends to be more sensitive to ionizing radiation than other head and neck cancers
The results showed that the expression patterns of both miRNAs and mRNAs could distinguish radioresistant CNE2-IR cells from radiosensitive CNE2 cells (Figure S1 and S2)
The expression levels of IL-8 were inverse correlation with miRNA-23a expression (Pearson’s correlation coefficient = 20.698, P,0.01) (Figure 4C). These results indicated that IL-8 might be a target of miRNA-23a in the nasopharyngeal carcinoma (NPC) tissues, and downregulaion of miRNA-203 and upregulation of IL8 might be involved in the clinical NPC radioresistance
Summary
Nasopharyngeal carcinoma (NPC) is an endemic disease in southern China and Southeast Asia, and tends to be more sensitive to ionizing radiation than other head and neck cancers. Understanding the mechanisms of NPC radioresistance is important for developing the personalized therapy and improving the patient prognosis. A radioresistant cell line (CNE2-IR) derived from poorly differentiated NPC cell line CNE2 was established, and comparative proteomic analysis of CNE2-IR and control CNE2 cells identified the four NPC radioresistance-related proteins [10]. These proteins are believed to play a role in the NPC radioresistance, our understanding of NPC radioresistance at a molecular level is limited. The purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance
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