Oral squamous cell carcinoma (OSCC) represents one of the most common head and neck cancer that with dire prognosis due partly to the lack of reliable prognostic biomarker. Here, we aimed to develop a CpG site-based prognostic signature through which we could accurately predict overall survival (OS) of patients with OSCC. We obtained OSCC-related DNA methylation and gene expression data sets from the public accessible Gene Expression Omnibus. Correlations between methylation level of CpG sites and OS of patients with OSCC were assessed by univariate Cox regression analysis followed by robust likelihood-based survival analysis on those CpG sites with permutation P < 0.05 for further screening the optimal CpG sites for OSCC OS prediction based on the risk score formula that composed of the methylation level of optimal CpG sites weighted by their regression coefficients. Besides, differential expression genes (DEGs) and differential methylation genes (DMGs) in OSCC samples compared with normal samples were obtained and shared genes were considered as vital genes in OSCC tumorgenesis and progression. As a result, two CpG sites including cg17892178 and cg17378966 that located in NID2 and IDO1, respectively, were identified as the optimal prognostic signatures for OSCC OS. In addition, 12 overlapping genes between DEGs and DMGs that closely associated with inflammation or blood and tissue development-related biological processes were obtained. In conclusions, this study should provide valuable signatures for OSCC diagnosis and treatment. K E Y W O R D SDNA methylation, gene expression, oral squamous cell carcinoma, overall survival, prognosis

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Background: Oral squamous cell carcinoma (OSCC) is a common malignancy in the oral cavity that represents a significant global health problem. Multivariate analysis has shown that long non-coding RNA LINC01296 plays an important role in cancer biology. However, the functions of LINC01296 in OSCC are still unknown. Methods:The RNA profiles and clinicopathological information of OSCC patients and healthy subjects were downloaded. The expression level and prognostic value of LINC01296 were assessed. The functions and pathways of LINC01296were explored using the Gene Set Enrichment Analysis (GSEA) and functional analysis. The expression of LINC01296 in OSCC tissues and cell lines was determined by RT-qPCR. MTS assay was used to evaluate cell growth. The migration and invasion capacities of cells were assessed by wound healing assay and Transwell assay. Results: LINC01296 was overexpressed in the TCGA-OSCC datasets. High LINC01296expression was strongly correlated with poor outcomes of OSCC patients. LINC01296 was overexpressed in OSCC tissues compared with para-carcinoma tissues. Moreover, the expression of linc01296 was higher in CAL-27, HSC-2, and SCC-25 cells than in normal human oral keratinocytes (NHOKs). Functional analysis suggested that LINC01296might be involved in the regulation of the Wnt and MAPK signaling pathways. Additionally, LINC01296 deficiency suppressed the growth, migration, and invasion of OSCC cells, whereas overexpression of TFAP2A-AS1 cause opposite results. Conclusion: Our study showed that LINC01296 promoted OSCC cell growth, migration, and invasion, suggesting that LINC01296 might be a potential therapeutic target for OSCC.

BackgroundCircular RNAs (circRNAs) play a key part in the progression of oral squamous cell carcinoma (OSCC). However, the role of circ‐BNC2 (circRNA ID hsa_circ_0086414) in OSCC progression is still unclear.MethodsPlasmid transfection was used to induce overexpression of circ‐BNC2. RNA expression of circ‐BNC2, microRNA‐142‐3p (miR‐142‐3p) and GNAS complex locus (GNAS) was detected by quantitative real‐time polymerase chain reaction. Protein expression was assessed by western blot assay or immunohistochemistry assay. Cell proliferation was investigated by 3‐(4,5‐dimethylthazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, colony formation assay and flow cytometry analysis. Cell migratory and invasive abilities and cell apoptosis were assessed by transwell assay and flow cytometry analysis, respectively. Oxidative stress was evaluated by superoxide dismutase activity detection assay, lipid peroxidation malondialdehyde assay and cellular reactive oxygen species assay. The binding relationship between miR‐142‐3p and circ‐BNC2 or GNAS was proved by dual‐luciferase reporter assay and RNA immunoprecipitation assay. The impacts of circ‐BNC2 overexpression on tumor growth in vivo were unveiled by a xenograft mouse model assay.ResultsCirc‐BNC2 expression was downregulated in OSCC tissues and cells when compared with adjacent healthy tissues and normal human oral keratinocytes. Circ‐BNC2 overexpression repressed the proliferation, migration and invasion of OSCC cells but induced cell apoptosis and oxidative stress. Additionally, circ‐BNC2 overexpression inhibited tumor growth in vivo. Furthermore, circ‐BNC2 bound to miR‐142‐3p, and miR‐142‐3p targeted GNAS. MiR‐142‐3p mimic attenuated circ‐BNC2 overexpression‐mediated effects on the proliferation, migration, invasion, apoptosis and oxidative stress of OSCC cells. The regulation of miR‐142‐3p in OSCC cell tumor properties involved GNAS. Further, circ‐BNC2 introduction promoted GNAS expression by inhibiting miR‐142‐3p.ConclusionCirc‐BNC2 suppressed OSCC malignant progression by upregulating GNAS expression in a miR‐142‐3p‐dependent manner, which suggested that circ‐BNC2 might be a novel target for OSCC therapy.

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