| Summary: | 博士 === 國立交通大學 === 生物科技學系 === 106 === Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer (OC) may be malignantly transformed from potentially malignant disorder and is often diagnosed at a late stage. The prognosis and survival rates for patients who diagnosed at late stage are worse than those at early stage. MicroRNAs (miRNAs) are a large family of about 20-22 nucleotide-long, non-coding, single-stranded RNA molecules that interact with target sequences to degrade or repress translation. They have also been documented to have roles in all of the cancer hallmarks by acting as oncogenes or tumor suppressor genes. Recently, miRNAs have been attractive as biomarkers in many aspects of clinical managements. The overall goal of conducting this study is to identify miRNA as potential biomarkers to early detect OC and the prognosis might therefore be improved.
This study consisted of two parts. First, plasma from normal, oral leukoplakia (OL), and OSCC patients were evaluated to identify potential circulating miRNA biomarkers. Small RNA sequencing was used to screen differently expressed miRNAs among the groups. Next, these miRNAs were validated with individual samples by quantitative real-time polymerase chain reaction (qRT-PCR) assays in the training phase and validation phase. Three miRNAs (miR-222-3p, miR-150-5p, and miR-423-5p) were identified as differentially expressed among groups; miR-222-3p and miR-423-5p negatively correlated with T stage, lymph node metastasis status, and clinical stage. A high diagnostic accuracy (Area under curve = 0.91) was demonstrated for discriminating OL from OSCC. Bioinformatics analysis revealed that miR-423-5p and miR-222-3p were significantly over-expressed in OC tissues and involved in various cancer pathways. The three plasma miRNA panel may be useful to monitor malignant progression from OL to OSCC and as potential biomarkers for early detection of OC.
In the second part, the meta-analysis of published miRNA profiling studies was carried out to compare the miRNA expression profiles between oral OC tissues and nontumor tissues to discover key regulatory miRNA in the tumorigenesis of OC. Collectively, 15 studies were included and 327 dysregulated miRNAs were discovered. By using Robust Rank Aggregation method, 11 meta-signature miRNAs were identified. Target genes of these miRNAs were predicted by 3 prediction algorithms and collected from miRtarbase. Subsequently, enrichment analysis by GeneCodis web tool indicated these genes were associated with cell signaling, cell regulation and cancer. Moreover, the expression patterns of these meta-signatures were confirmed TCGA miRNA expression data. MiR-1-3p, miR-133a-3p, miR-99a-5p and miR-196a-5p displayed differential expression level between early and late stage of OC while miR-31-5p, miR-31-3p, miR-135b-5p, miR-133a-3p, miR-99a-5p and miR-1-3p correlated with overall survival rate of OC. This study provides the understanding of essential miRNAs in the development of OC and potential prognostic biomarkers of OC.
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