N 6 -Adenosine Methyltransferase METTL3 is a Positive Prognostic Biomarker in Lung Squamous Cell Carcinoma

Background: N6-methyladenine is the most common modification of mRNA and IncRNA in higher organisms. m6A has been confirmed to be related to the formation and progression of tumors and m6A-related genes can be used as prognostic biomarkers in a variety of tumors. However, there have been no similar studies on lung squamous cell carcinoma. The main purpose of this study was aimed to explore the differential expression of m6A-related genes in lung squamous cell carcinoma tissues and its relationship with patient clinical prognosis.  Methods: We integrated three m6A writers that catalyze the methylation of adenine on mRNA molecules. The training set including 501 patients with LUSC was collected from The Cancer Genome Atlas database and the test set including 181 patients with LUSC was collected from the Gene Expression Omnibus database. Based on the expression level of the m6A methylase gene, we established a tumor subgroup and risk-prognosis model to quantify the risk index and long-term patient prognosis, which were confirmed by principal component analysis and receiver operating characteristic curve analysis. After lung squamous cell carcinoma tissue specimens were obtained during surgery, immunohistochemistry was used to verify the results in vitro.  Results: The results of the study showed that the expression of the three m6A methylases in tumor tissues and normal tissues was significantly different (P<0.05). The survival-prognostic model based on METTL3 gene expression showed better predictive performance (AUC: 0.706). Patients in the high-risk and low-risk groups exhibited significant differences in terms of survival time and 5-year and 10-year survival rates. Immunohistochemistry revealed that patients with high METTL3 expression exhibited a longer survival time than those with low METTL3 expression. Conclusions: Our study showed that the expression level of m 6 A methylase in tumor tissues was much higher than that in normal tissues. At the same time, the molecular phenotype based on the expression of METTL3 may be an independent risk factor affecting the prognosis of lung squamous cell carcinoma. These findings not only prove the important role of m6A methylase in lung squamous cell carcinoma, but are also expected to provide more accurate prognostic assessment and individualized treatment for patients with lung squamous cell carcinoma.  Funding: This study was supported by the Taishan Scholar foundation (No. tshw201502061). Declaration of Interest: The authors declare that they have no conflicts of interest. Ethical Approval: The Affiliated Hospital of Qingdao University Institutional Review Board approved this study, and all study subjects provided informed consent..