Identification of Stage-Specific microRNAs that Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Human Genetics with Epigenetics and Utilizing an Animal Model

Author:

Gintoni Iphigenia1234,Vassiliou Stavros3,Chrousos George P.4ORCID,Yapijakis Christos1234ORCID

Affiliation:

1. Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, 115 27 Athens, Greece

2. Department of Molecular Genetics, Cephalogenetics Center, 176 72 Athens, Greece

3. Department of Oral and Maxillofacial Surgery, School of Medicine, National Kapodistrian University of Athens, Attikon Hospital, 124 62 Athens, Greece

4. University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory, “Aghia Sophia” Children’s Hospital, 115 27 Athens, Greece

Abstract

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.

Publisher

MDPI AG

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