The Role of Critical N6-Methyladenosine-Related Long Non-Coding RNAs and Their Correlations with Immune Checkpoints in Renal Clear Cell Carcinoma

Wen Deng; Gongxian Wang; Huanhuan Deng; Yan Yan; Ke Zhu; Ru Chen; Xiaoqiang Liu; Luyao Chen; Tao Zeng; Bin Fu

doi:10.2147/IJGM.S344771

The Role of Critical N6-Methyladenosine-Related Long Non-Coding RNAs and Their Correlations with Immune Checkpoints in Renal Clear Cell Carcinoma

Int J Gen Med. 2021 Dec 14:14:9773-9787. doi: 10.2147/IJGM.S344771. eCollection 2021.

Authors

Wen Deng^#¹, Gongxian Wang^#¹, Huanhuan Deng^#², Yan Yan^#³, Ke Zhu^#¹, Ru Chen^{1

4}, Xiaoqiang Liu¹, Luyao Chen¹, Tao Zeng², Bin Fu¹

Affiliations

¹ Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China.
² Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China.
³ Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China.
⁴ Department of Urology, The First Hospital of Putian City, Putian City, Fujian Province, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: This study aimed to evaluate the functions of critical N6-methyladenosine (m6A)-related long non-coding RNAs (lncRNAs) and their correlations with immunotherapeutic targets in clear cell renal cell carcinoma (ccRCC).

Methods: m6A-related lncRNAs were analyzed using the dataset from The Cancer Genome Atlas database via Pearson correlation analysis. Then, their prognostic functions in patients with ccRCC were determined via univariate Cox analysis. A prognostic m6A-related lncRNA signature (MRLS) in ccRCC was established using the least absolute shrinkage and selection operator (LASSO) Cox regression model. In addition, the correlations between these prognostic m6A-related lncRNAs with immune checkpoints were further evaluated in clinical samples.

Results: MRLS was established by the LASSO Cox regression model on the basis of seven prognostic m6A-related lncRNAs. The risk score for each patient was calculated using the MRLS model, and the patients were further stratified into high- and low-risk subgroups. The MRLS model was validated with a robust prognostic ability by the stratification analysis. On the basis of age, grade, stage, and risk score, a nomogram was developed with a strong reliability in forecasting the overall survival percentages of the patients with ccRCC. Moreover, seven prognostic m6A-related lncRNAs enrolled in the MRLS model were found to be correlated with various immunotherapeutic targets, namely, PD-1, PD-L1, CTLA4, and LAG3, and the expression levels of which in the high-risk subgroup were significantly higher than those in the low-risk subgroup. The significant correlations between LINC00342 and the aforementioned immunotherapeutic targets were also confirmed in clinical samples.

Conclusion: In this study, seven m6A-related lncRNAs were identified as potential biomarkers for forecasting the prognosis of patients with ccRCC and evaluating the efficacy of immunotherapy for these patients. Furthermore, a prognostic and predictive MRLS model with a high reliability was constructed to predict the overall survival probability of patients with ccRCC.

Keywords: N6-methyladenosine modification; immunotherapy; long non-coding RNA; prognosis; renal cell carcinoma.

Grants and funding

This study was supported by the National Natural Science Foundation of P.R. China (Grant Nos. 81560419, 81960512, and 81760457), Jiangxi Provincial “Double Thousand Plan” Fund Project (Grant No. jxsq2019201027), Key Project of Natural Science Foundation of Jiangxi Province (20212ACB206013), and Youth Project of Natural Science Foundation of Jiangxi Province (20212BAB216037).