N7-methylguanosine regulatory genes well represented by METTL1 define vastly different prognostic, immune and therapy landscapes in adrenocortical carcinoma

• Published in: American journal of cancer research Vol. 13; no. 2; pp. 538 - 568
• Main Authors: Xu, Fangshi, Cai, Danrui, Liu, Shanshan, He, Kaini, Chen, Jing, Qu, Li, Chong, Tie, Li, Xueyi, Ren, Bincheng
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01.01.2023
• Subjects: Original; N7-methylguanosine; adrenocortical carcinoma; METTL1; prognosis; risk signature
• ISSN: 2156-6976; 2156-6976

Although N7-methylguanosine (m7G) is one of the most frequent RNA modifications, it has received little attention. Adrenocortical carcinoma (ACC) is a highly malignant and easily metastatic tumor, eagerly needing for novel therapeutic strategy. Herein, a novel m7G risk signature (METTL1, NCBP1, NUDT1 and NUDT5) was constructed using the Lasso regression analysis. It possessed highly prognostic value and could improve the predictive accuracy and clinical making-decision benefit of traditional prognostic model. Its prognostic value was also successfully validated in GSE19750 cohort. Through CIBERSORT, ESTIMATE, ssGSEA and GSEA analyzes, high-m7G risk score was found to be closely associated with increased enrichment of glycolysis and suppression of anti-cancer immune response. Therapeutic correlation of m7G risk signature was also investigated using tumor mutation burden, the expressions of immune checkpoints, TIDE score, IMvigor 210 cohort and TCGA cohort. m7G risk score was a potential biomarker for predicting the efficacy of ICBs and mitotane. Furthermore, we explored the biofunctions of METTL1 in ACC cells through a series of experimentations. Overexpression of METTL1 stimulated the proliferation, migration and invasion of H295R and SW13 cells. Immunofluorescence assays revealed that the infiltrating levels of CD8+ T cells was lower and that of macrophages was higher in clinical ACC samples with high METTL1 expression compared to that in low expression ones. Silencing METTL1 could significantly inhibited tumor growth in mouse xenograft model. Western blot assays showed that METTL1 positively regulated the expression of glycolysis rate-limiting enzyme HK1. Finally, miR-885-5p and CEBPB were predicted as the upstream regulators of METTL1 through data mining of the public databases. In conclusions, m7G regulatory genes well represented by METTL1 profoundly affected the prognosis, tumor immune, therapeutic outcomes, and malignant progression of ACC.