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.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates reaching 60%, mainly due to its excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules exhibiting expressional dysregulation in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting seed-matching and the reverse interplay between miRNA levels and their target genes’ expression. Incorporating gene-expression data from our group’s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia, and early invasion, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is under-expressed in dysplasia and early invasion. The malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p, and miR-34a-5p. The identification of stage-specific miRNAs may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite therapeutic advances, highlighting the need for a better understanding of its molecular background. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful as non-invasive biomarkers. A plethora of findings regarding miRNA expression have been generated, posing challenges for their interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important miRNA molecules by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed a custom panel of 15 major oncogenes and a second panel of 5 major tumor suppressor genes. Following a miRNA/target interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules, which target the majority of each gene panel and are 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 expressional patterns, their verified targets and the signaling pathways affected by their dysregulation in OSCC, are thoroughly discussed in this review.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates that reach 60%, mainly due to an excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules reported to be dysregulated in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting the reverse interplay between miRNA-levels and their target-genes’ expression. Incorporating gene expression data from our group’s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia and early-invasion OSCC, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is underexpressed in dysplasia and early-invasion. Malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p and miR-34a-5p. The identification of stage-specific miRNA molecules may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Background: Oral squamous cell carcinoma (OSCC) is a highly aggressive neoplasm characterized by grim survival outcomes, despite significant therapeutic advances. Mortality rates (up to 70%) have remained unaltered for decades, predominantly due to profound diagnostic delays. These derive from the asymptomatic nature of the early stages of oral carcinogenesis and the emergence of dysplastic areas in previously benign lesions, acting as the bridge to malignant transformation. Hence, the establishment of reliable salivary biomarkers is crucial for non-invasive OSCC detection, even from the premalignant stage of dysplasia. Based on our previous bioinformatic research identifying stage-specific miRNAs throughout OSCC progression, which yielded miR-34a-5p as the most significant, we aimed to experimentally investigate its role in oral oncogenesis and explore its stage-reflecting biomarker potential for liquid biopsy. Methods: The expression of miR-34a was evaluated using quantitative real-time PCR in saliva samples from 9 patients with oral premalignant dysplastic lesions, 10 patients with OSCC and 10 healthy controls. The diagnostic accuracy of miR-34a expression profiles was assessed using ROC-curve analyses. Results: The expression of salivary miR-34a differed significantly across the studied groups, demonstrating a steep decrease in the presence of epithelial premalignant dysplasia, significant upregulation in OSCC and intermediate levels in normal oral mucosa (p < 0.001). The ROC results indicate strong diagnostic performance for the detection of oral dysplasia (AUC = 0.93; p < 0.001), OSCC (AUC = 0.77; p = 0.01) and excellent accuracy for the discrimination between premalignant and OSCC lesions (AUC = 0.98; p < 0.001). Conclusions: Our findings reveal a state-dependent dysregulation of miR-34a in oral carcinogenesis, suggesting its complex role as a pathogenetic agent that allows for malignant transformation through its diminished expression, and as a secondary reactive mechanism attempting to suppress tumor development. Salivary miR-34a holds great, stage-specific diagnostic potential, thereby reflecting the health state of oral mucosa in real time.

Pediatric thrombosis (PT) represents a rare condition that can manifest from neonatal life to adolescence, encompassing life-threatening complications. Its pathogenesis is attributed to immature hemostasis in conjunction with environmental and genetic factors, predominantly including those resulting in increased levels of plasminogen activator inhibitor 1 (PAI-1), the principal inhibitor of fibrinolysis, which is subject to upstream regulation by angiotensin-converting enzyme (ACE). Although the implication of microRNAs (miRNAs), epigenetic modulators of gene expression, has been demonstrated in adult thrombosis, evidence is lacking in the pediatric setting. Here, we investigated the involvement of two miRNA regulators of PAI-1 (SERPINE1 gene) in PT, in relation to clinical and genetic parameters that induce PAI-1 fluctuations. Following bioinformatic target-prediction, miRNA expression was assessed by quantitative real-time PCR in serum-samples of 19 pediatric patients with thrombosis (1–18 months post-incident), and 19 healthy controls. Patients were genotyped for the SERPINE1-4G/5G and ACE-I/D polymorphisms by PCR-based assays. Genotypic and thrombosis-related clinical data were analyzed in relation to miRNA-expression. Two miRNAs (miR-145-5p, miR-34a-5p) were identified to target SERPINE1 mRNA, with miR-34a additionally targeting the mRNA of ACE. The expression of miR-34a was significantly decreased in patients compared to controls (p = 0.029), while no difference was observed in miR-145 expression. Within patients, miR-34a expression demonstrated a peak 1–3 months post-thrombosis and was diminished upon treatment completion (p = 0.031), followed by a slight long-term increase. MiR-34a levels differed significantly by thrombosis site (p = 0.019), while a significant synergistic interaction between site and onset type (provoked/unprovoked) was detected (p = 0.016). Finally, an epistatic modification was observed in cerebral cases, since double homozygosity (4G/4G + D/D) led to a miR-34 decrease, with D/D carriership reversing the 4G/4G-induced upregulation of miR-34a (p = 0.006). Our findings suggest that in pediatric thrombosis, downregulation of miR-34a is indicative of impaired fibrinolytic capacity, attributed to deficient regulation of the inhibitory ACE/PAI-1 axis.