Nasopharyngeal carcinoma (NPC) is posing a serious health problem worldwide. The association between its pathogenesis and microRNAs (miRNA) has not been elucidated. In this study, miRNA expression profiling was performed to screen the miRNA expression changes in 8 NPC tissues and 4 normal nasopharyngeal tissues. Thirty-four miRNAs were identified to be differentially expressed; of these, one miRNA (miR-18a) was overexpressed and 33 miRNAs (miR-34b, miR-34c, let-7 family, etc.) were underexpressed in NPC tissues compared to the normal samples. Validation was performed by real-time quantitative PCR for two altered miRNAs (miR-34b and let-7g) and one non-differentially expressed miRNA (miR-30c). Unsupervised hierarchical clustering analysis showed that the aberrant miRNAs were correlated with the clinical stage of NPC patients. In addition to several biological pathways that are well characterised in NPC and which were significantly targeted by the underexpressed miRNAs, two novel pathways, nervous system development and sensory perception of sound, were identified to be strongly associated with NPC development. Furthermore, a c-Myc centered miRNA regulatory network was inferred in NPC. Our study reveals that aberrantly expressed miRNAs play important roles in NPC tumorigenesis and may serve as potential targets for novel therapeutic strategies in the future.
"Previous evidences have implicated the importance of miRNAs dysregulation in NPC tumorigenesis. The miRNA aberrant expression could promote an aggressive tumor phenotype by changing the expression of mRNA targets (Hu et al., 2009; Li et al., 2011 "
"In the beginning of our study, we actually failed to find miRNAs targeting TGFBR2 in NPC using a global miRNA expression profiling analysis of clinical samples (data not shown but available in GEO database. Accession Number is GSE42945), similar to other studies [58,59]. Alternatively, based on this miRNA expression profiling data, we next re-classified clinical samples into high and low TGFβR2 expression NPC subgroups and normal control group, and interestingly discovered a cluster set of TGFβR2-associated miRNAs (miR-93, miR-20a, miR-20b and miR-18a), which all belong to miR-17-92 cluster and its paralogues. "
[Show abstract][Hide abstract] ABSTRACT: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-beta receptor II (TGFbetaR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFbetaR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.
We firstly evaluated the clinical signature of TGFbetaR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFbetaR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFbetaR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFbetaR2 down-regulation.
TGFbetaR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFbetaR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFbetaR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-beta signaling and the activation of PI3K/Akt pathway by suppressing TGFbetaR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFbetaR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFbetaR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFbetaR2 in NPC.
The present study reports an involvement of miR-93-mediated TGFbetaR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
Molecular Cancer 03/2014; 13(1):51. DOI:10.1186/1476-4598-13-51 · 4.26 Impact Factor
"Various genome-wide miRNA expression profiling studies using microarray-based approaches have provided us with abundant information on the phenotypic characteristics of cancers -. Distinct patterns of miRNA expression and special miRNA signatures were found to be associated with the clinical and pathological characteristics of NPC and the patient outcome –. Nevertheless, few miRNA expression profiling studies have been focused on the tumor radioresistance –. To our knowledge, there has been no report on miRNA expression profiling study of NPC radioresistance. "
[Show abstract][Hide abstract] ABSTRACT: 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.
We 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.
THE 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.
We 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.
PLoS ONE 01/2014; 9(1):e87767. DOI:10.1371/journal.pone.0087767 · 3.23 Impact Factor
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