Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed.

Identification of Stage-Specific microRNAs That Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Genetics and Epigenetics

“…The present study involves the integration of human miRNA-expression data from OSCC tissue and/or saliva samples with stage-specific gene expression data from a highly representative animal model for sequential oral oncogenesis, developed by our research team [30,31]. The incorporated epigenomic and genomic data were integrated by utilizing a combinatory in silico methodology that was developed by our group in 2023, for the identification of the 5 most disease-specific miRNAs for OSCC, among 239 dysregulated molecules, by strategically bridging genetics with miRNAepigenetics [8]. Both pieces of research are briefly reviewed prior to the comprehensive presentation of the methods applied in the current study.…”

“…The identification of the most significant and indicative miRNA molecules for OSCC was determined based on the combination of the following variables: I) Their capacity to target and potentially regulate multiple crucial OSCC genes simultaneously, and II) their experimentally verified dysregulation pattern (either up-or down-regulation) in OSCC, which shall be reverse to the one of their target-genes [8].…”

“…After applying further filtering to the acquired data, we identified a particular subset of miRNAs that are expected to target at least 60% of the fifteen oncogenes and over 60% of the five tumor suppressor genes included in the generated panels. Ultimately, the molecules that successfully passed through the previous filtering processes for each panel, but also demonstrated a reverse dysregulation pattern in OSCC compared to their target-genes, were yielded as the most OSCC-specific miRNAs [8].…”

“…Our previous bioinformatic research on disease-specific miRNA molecules for OSCC in general [8] encompassed the creation of two databases, including the total of significantly upregulated and downregulated miRNAs that have been reported in the OSCC-related literature up until June 20, 2023, providing a detailed picture of the literature of that time on miRNA expression patterns in OSCC and served as starting data pool for the conducted analyses. To include novel additions of dysregulated molecules in the current literature, we conducted an additional PubMed search employing the same criteria.…”

“…Only in 2023, 377.713 new OSCC cases, as well as 177.757 deaths were globally reported [4][5][6]. Despite advancements in treatment, the prognosis for OSCC remains OSCC-derived specimens, to functionally document their putative regulatory role in OSCC development, through the inverse relations between miRNA levels and the expression of their targetgenes [8].…”