The increase of oncogenic miRNA expression in tongue carcinogenesis of a mouse model

• The dysregulation of oncogenic miRNAs occurs in murine tongue tumorigenesis.
• Increased miR-21, miR-31 and miR-146a are early markers for the liquid biopsies.
• The targeting against EGFR or oncogenic miRNAs could be pre-clinically tested.

SummaryObjectivesThis study investigated the oncogenic miRNA level in the tissue and biofluids in the Nitroquinoline 1-Oxide (4NQO)-induced mouse tongue carcinogenesis model for potential diagnostic or therapeutic application.Materials and methodsThe histological examination, immunohistochemistry, in situ hybridization, quantitative PCR analysis and bioinformatic algorithms were performed to unravel the signaling activation and miRNA expression in female murine samples.ResultsThe increase of miR-21 and miR-31 staining, and EGFR activation paralleled the severity of 4NQO-induced epithelial pathogenesis in tongue epithelium. A progressive increase of miR-21, miR-31 and miR-146a in both saliva and plasma samples was also noted. miR-31 was the earliest emerging miRNA in the saliva. The increase of plasma miR-146a, miR-184 and miR-372 was detectable early in the induction, and it was particularly eminent at the most advanced lesion state. The combined analysis of the multiple oncogenic miRNAs in the plasma signified a potent discriminative capacity between normal and pathological states. As the blockage of EGFR or AKT activation drastically reverted the miR-21, miR-31 and miR-146a expression induced by 4NQO in human oral carcinoma cell lines, the results implicated a mechanistic linkage of the oncogenic miRNAs’ induction through EGFR/AKT activation.ConclusionsIn this study, we show the dysregulation of oncogenic miRNAs in murine tongue tumorigenesis, which simulates human counterparts. Increased multiple miRNAs in the biofluids may be valuable non-invasive markers in detecting oral carcinogenesis at an early stage. This animal model may also be useful for developing liquid biopsies and prevention strategies against oral carcinoma by abrogating EGFR or oncogenic miRNAs.