METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma

Tianbo Xu; Su Gao; Hailong Ruan; Jingchong Liu; Yuenan Liu; Di Liu; Junwei Tong; Jian Shi; Hongmei Yang; Ke Chen; Xiaoping Zhang

doi:10.3389/fgene.2021.609174

METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma

Front Genet. 2021 May 28:12:609174. doi: 10.3389/fgene.2021.609174. eCollection 2021.

Authors

Tianbo Xu¹, Su Gao^{2

3}, Hailong Ruan¹, Jingchong Liu¹, Yuenan Liu¹, Di Liu¹, Junwei Tong¹, Jian Shi¹, Hongmei Yang⁴, Ke Chen¹, Xiaoping Zhang¹

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Institute of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by its insensitivity to chemoradiotherapy and lacks effective diagnostic and prognostic biomarkers. In this study, we focused on the role of m6A RNA methylation regulators for tumor immunity. Based on the expression of 20 m6A regulators, consensus clustering was performed to divide patients into cluster1/cluster2 and showed that there was a survival difference between the two clusters. Through cox regression analysis, five hub m6A regulators were screened to construct a risk model. Further analysis showed that the risk score was an independent prognostic factor. GSEA, GSVA, and KEGG analysis revealed that immune cell pathways played a critical role between the high risk group and low risk group. Combined with CIBERSORT and survival analysis, five hub tumor-infiltrating immune cells (TIICs) were identified for further study. Meanwhile, correlation analysis indicated that IGF2BP2 was positively associated with activated memory CD4 T cell and METTL14 was negatively correlated to the regulatory T cell. Therefore, IGF2BP2 and METTL14 were regarded as key genes. Further study verified that only METTL14 possessed good diagnostic and prognostic value. Then, GSEA exhibited that METTL14 was mainly enriched in chemokine related pathways. We also found that CCL5 was negatively correlated to METTL14 and might serve as a potential target of METTL14. In conclusion, these findings suggest that the METTL14/CCL5/Tregs axis is a potential signaling pathway for regulating tumor immunity, and might become novel therapeutic targets for ccRCC.

Keywords: CCL5; METTL14; clear cell renal cell carcinoma; m6A RNA methylation; regulatory T cell; tumor immunity; tumor progression.