Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism

Abstract

BackgroundThe advantages and utility of microRNAs (miRNAs) as diagnostic and prognostic cancer markers is at the vanguard in recent years. In this study, we attempted to identify and validate the differential expression of miRNAs in oral squamous cell carcinoma (OSCC), to correlate their expression with the clinico-pathological profile of tumours and to identify the signaling pathways through which the aberrantly expressed miRNAs effect tumourigenesis.MethodsmiRCURY LNA™ array with probes specific to 1168 miRNAs and TaqMan assays specific for 10 miRNAs was employed to evaluate and validate miRNA expression in a discovery cohort (n = 29) and validation cohort (n = 61) of primary OSCC tissue specimens, respectively. A computational pipeline with sequential integration of data from miRTarBase, CytoScape, UniProtKB and DIANA-miRPath was utilized to map the target genes of deregulated miRNAs and associated molecular pathways.ResultsMicroarray profiling identified 46 miRNAs that were differentially expressed in OSCC. Unsupervised clustering demonstrated a high degree of molecular heterogeneity across the tumour samples as the clusters did not represent any of their clinico-pathological characteristics. The differential expression of 10 miRNAs were validated by RT-qPCR (let-7a, let-7d, let-7f and miR-16 were downregulated while miR-29b, miR-142-3p, miR-144, miR-203, and miR-223 were upregulated in OSCC; the expression of miR-1275 was variable in tumours, with high levels associated to regional lymph node invasion; additionally, miR-223 exhibited an association with advanced tumour stage/size). In silico analyses of the experimentally confirmed target genes of miRNAs revamp the relationship of upregulated miRNAs with tumour suppressor genes and of downregulated miRNAs with oncogenes. Further, the differentially expressed miRNAs may play a role by simultaneously activating genes of PI3K/Akt signaling on one hand and by repressing genes of p53 signaling pathway on the other.ConclusionsThe identified differentially expressed miRNAs and signaling pathways deregulated in OSCC have implications for the development of novel therapeutic strategies. To the best of our knowledge, this is the first report to show the association of miR-1275 with nodal invasion and the upregulation of miR-144 in OSCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0512-8) contains supplementary material, which is available to authorized users.

Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5

“…Ning Y, et al, found that let-7d was downregulated in ovarian cancer tissues compared with normal ovarian tissues [22]. Let-7d was also reported to be downregulated in oral squamous cell carcinoma [33] and renal cell carcinoma [24], which was consistent with our results in breast cancer. However, in some cases of head and neck squamous cell carcinoma (HNSCC), let-7d was significantly upregulated in tumor tissue [34].…”

Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma

“…Oral carcinogenesis arises through the accumulation of genetic and epigenetic changes, including alterations in the expression of coding and non-coding RNAs (3,4). Oral cancer types express a specific miRNA portfolio, which contributes to maintain the epithelial characteristics of the cells (5,6). …”

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

“…By analysis of the miRNA expression profiles of OSCC tumors and normal oral mucosal samples, Soga’ et al showed that OSCC tissues have a unique miRNA profile pattern when compared with that in normal tissues [8]. In another study, Manikandan’ et al identified 46 miRNAs that were differentially expressed in OSCC [9]. Likewise, Siow’ et al identified 15 upregulated and 4 downregulated miRNAs in OSCC as compared with normal tissues and miR-375 was validated as the most down-regulated miRNA [10].…”