Tumor Suppressive Circular RNA-102450: Development of a Novel Diagnostic Procedure for Lymph Node Metastasis from Oral Cancer

SIMPLE SUMMARY: Circular RNAs (circRNAs) consist of covalently closed structures without a free 3′ poly(A) tail or 5′ cap. Due to their loop structures, circRNAs are largely stable and resistant to RNA degradation by endonucleases. Therefore, they have much longer circulatory half-lives compared with linear RNAs, such as microRNA and long non-coding RNA. CircRNAs have multiple microRNA binding sites, and circRNA binding leads to regulation of the expression of those miRNAs and their target genes by acting as a competing endogenous RNA. However, the underlying molecular mechanisms and clinical correlation between circRNAs and tumor progression are not well understood. In the present study, we identified circRNA-102450 as a novel tumor suppressor and potential biomarker of regional lymph node metastasis from OSCC using liquid biopsy-based droplet digital PCR, a highly sensitive method for absolute quantification. ABSTRACT: Circular RNAs (circRNAs), which form as covalently closed loop structures, have several biological functions such as regulation of cellular behavior by adsorbing microRNAs. However, there is limited information of circRNAs in oral squamous cell carcinoma (OSCC). Here, we aimed to elucidate the roles of aberrantly expressed circRNAs in OSCC. CircRNA microarray showed that circRNA-102450 was down-regulated in OSCC cells. Clinical validation of circRNA-102450 was performed using highly sensitive droplet digital PCR in preoperative liquid biopsy samples from 30 OSCC patients. Interestingly, none of 16 studied patients with high circRNA-102450 had regional lymph node metastasis (RLNM), whereas 4 of 14 studied patients (28.5%) with low expression had pathologically proven RLNM. Overexpressed circRNA-102450 significantly inhibited the tumor metastatic properties of cell proliferation, migration, and invasion. Furthermore, circRNA-102450 directly bound to, and consequently down-regulated, miR-1178 in OSCC cells. Taken together, circRNA-102450 has a tumor suppressive effect via the circRNA-102450/miR-1178 axis and may be a novel potential marker of RLNM in OSCC patients.