METTL3 upregulation in NSCLC chemoresistance via m6A-AKT1 pathway

Abstract

Background Treatments for non-small cell lung cancer (NSCLC) have improved tremendously, but therapeutic resistance is a common and major clinical challenge in treatment. Methyltransferase-like 3 (METTL3) is a ribonucleic acid (RNA) methyltransferase that has crucial functions in the development and progression of cancers, including drug resistance, by regulating N6-methyladenosine (m 6 A) modification. However, the role of METTL3 in the progression and drug resistance of NSCLC is poorly understood. Methods The expression levels of METTL3 and AKT serine/threonine kinase 1 (AKT1) in NSCLC tissues were detected using quantitative real-time PCR (RT-qPCR), Western blots, and immunohistochemical assays. The m 6 A levels of AKT1 messenger RNA (mRNA) in NSCLC tissues were detected using m 6 A methylated RNA immunoprecipitation–quantitative polymerase chain reaction. Results The expression levels of METTL3 and the AKT1 protein were significantly increased in NSCLC tissues, and m6A expression levels of AKT1 mRNA were dramatically upregulated in NSCLC tissues. Additionally, METTL3, AKT1 protein, and m 6 A levels of AKT1 mRNA were overexpressed in chemoresistant NSCLC samples, and high expression levels of METTL3 and AKT1 were correlated with poor patient survival, especially in chemoresistant NSCLC patients. Further, AKT1 protein expression and m 6 A levels of AKT1 mRNA were positively correlated with METTL3 expression, and AKT1 protein expression was positively correlated with m 6 A levels of AKT1 mRNA. Moreover, METTL3 and AKT1 protein expression levels were significantly associated with cisplatin susceptibility, tumor, node, metastasis stage, and lymph node metastasis. Conclusions Taken together, our results indicate that METTL3 contributes to the progression and chemoresistance of NSCLC by promoting AKT1 protein expression through regulating AKT1 mRNA m6A levels, and may provide an efficient therapeutic intervention target for overcoming chemoresistance in NSCLC.