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Expression of m6A methylation-modified circRNA in malignant transformation of oral leukoplakia tissue

ABSTRACT: Objective This study aimed to investigate the expression and clinical significance of N6-methyladenosine (m6A) modification of circular RNA (circRNA) in oral leukoplakia (OLK) and oral squamous carcinoma cell (OSCC) tissues. Methods Using methylation RNA immunoprecipitation high-throughput sequencing technology (MeRIP-seq) and RNA high-throughput sequencing technology (RNA-seq), the first circRNA transcriptome analysis for detecting m6A methylationome profiles in OLK and OSCC tissues was obtained, followed by bioinformatics analysis. The qRT-PCR technique and protein immunoblotting technique were used to detect the expression of m6A methylesterase in OLK versus OSCC tissues. Results In this study, 275 differential m6A methylation peaks were identified in OLK and OSCC, among which 193 peaks were up-regulated and 82 were down-regulated. Additionally, 198 differential m6A methylation modified circRNAs were observed, with 127 up-regulated and 71 down-regulated (FC ≥ 2, P < 0.05). Most of the identified circRNAs that underwent m6A methylation alterations were derived from overlapping regions. It was found that the differential expression of circRNAs was not correlated with the joint analysis of significantly different m6A-circRNAs between the two groups. Furthermore, downregulation of mETTL14 and FTO protein levels was observed in OSCC tissues, although there were no discernible alterations in RNA levels. Conclusion Our study suggests that m6A methylation modification of circRNA may play a role in the development of oral leukoplakia, and that METTL14 and FTO may be important methylation enzymes that influence the development of oral leukoplakia. These findings may open up new research directions for in-depth investigations to clarify the molecular mechanisms of OLK carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243097 | GEO | 2023/09/20

REPOSITORIES: GEO

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Project description:Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in-vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and Quantitative Methylation Specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage-design consisting of Discovery and Prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (k=0.64), HOXA9 (k=0.60), NID2 (k=0.60), and EDNRB (k=0.60) had a moderate to substantial agreement with clinical diagnosis in the Discovery screen. HOXA9 had 68% sensitivity, 100% specificity and a 0.81 AUC. NID2 had 71% sensitivity, 100% specificity and a 0.79 AUC. In the Prevalence screen HOXA9 (k=0.82) and NID2 (k=0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity and a 0.97 AUC. In saliva from OSCC cases and controls HOXA9 had 75% sensitivity, 53% specificity and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity and a 0.73 AUC. This Phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies. The 12 samples analyzed comprise equal numbers of three tissue-types: Primary oral squamous cell carcinoma, Oral leukoplakia and Normal oral mucosa. Gender, age and smoking-status were approximately equally represented in these goups. Normal oral mucosa served as a control.

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Expression of m6A methylation-modified circRNA in malignant transformation of oral leukoplakia tissue

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