Abstract
It has been demonstrated that circ_0001874 and circ_0001971 are potential biomarkers for the diagnosis of oral squamous carcinoma (OSCC). MiR-186 was reported to serve as a tumor suppressor in OSCC, and the down-regulation of miR-186 was reported to lead to higher expression of oncogenic factor SHP2 and the activation of growth promoting signaling. In this study, we aimed to explore the possible molecular role of circ_0001874 and circ_0001971 signaling in the pathogenesis of OSCC. RT-qPCR, Western blot, online bioinformatics tools and luciferase assay were utilized to study the molecular signaling pathways of circ_0001874 and circ_0001971. MTT assay and FCM assay were performed to investigate the synergistic effect of circ_0001971 and circ_0001874 on cell proliferation and apoptosis. By observing the effect of different miRNAs on the levels of circ_0001847 and circ_0001971, it was identified that circ_0001847 and circ_0001971 respectively sponged the expression of miR-296 and miR-186 via binding to these miRNAs. Also, SHP2 mRNA and PLK1 mRNA were respectively targeted by miR-186 and miR-296-5p. We also established two signaling pathways, i.e., circ_0001971/miR-186/SHP2 and circ_0001874/miR-296-5p/PLK1, and validated the synergistic effect of circ_0001971 and circ_0001874 via observing their positive effect on cell proliferation and negative effect on cell apoptosis. The expression of miR-186 and miR-296-5p was generally lower in saliva of OSCC patients compared with that in OLK patients, while the expression of miR-186 and miR-296-5p was specifically up-regulated in saliva of OSCC patients. In conclusion, the finding of this study demonstrated that the relative level of hsa_circ_0001971 and hsa_circ_0001874 were different in the saliva of OSCC patients and could be used as predictive biomarkers for the development of OSCC. Furthermore, oncogenic effects of hsa_circ_0001971 and hsa_circ_0001874 in the development of OSCC might be, at least partially, mediated by its downstream signaling pathways including hsa_circ_0001971/microRNA-186/SHP2 and hsa_circ_0001874/microRNA-297/PLK1.
Highlights
We recruited two group of patients, i.e., a total of 135 oral squamous carcinoma (OSCC) patients and a total of 105 oral leukoplakia (OLP) patients, who were divided into two groups, i.e., an OSCC group (N = 135) and an OLK group (N = 105)
We selected candidate miRNAs for further functional analysis based on the predicted target genes of the miRNAs, i.e. only those miRNAs with possible target gene(s) involved in the tumorigenesis of OSCC were selected
We found that the expression of miR-186 and miR-296-5p was significantly down-regulated in saliva of OSCC patients after operation
Summary
By targeting PLK1 expression, the presence of miR-296-5p can block the growth of PTC cells while promoting their apoptosis[12]. In OSCC, SHP2 was discovered to become overexpressed in cancer cells, but the inhibition of SHP2 decreased the rate of cell p roliferation[16] Both the luciferase assay and Western blotting confirmed the role of SHP2 as a miR-186 target. Considering that hsa_circ_0001874 and hsa_circ_0001971 could be potentially used as biomarkers for the diagnosis of OSCC9, and miR-296 and miR-186 could interact with hsa_circ_0001874 and hsa_circ_0001971 respectively (circinteractome.nia.nih.gov), we hypothesized that upregulation of hsa_circ_0001874 and hsa_ circ_0001971 may functionally contribute to the tumorigenesis of OSCC via modulating the expression of miR296 and miR-186, as well as their downstream effectors such as SHP2 and PLK1. We aimed to explore the possible molecular mechanism underlying the tumorigenic effect of hsa_circ_0001874 and hsa_circ_0001971 in the pathogenesis of OSCC
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