Research Paper Volume 13, Issue 8 pp 11919—11941
Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma
- 1 Department of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- 2 Department of Urology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710000, China
Received: November 19, 2020 Accepted: March 14, 2021 Published: April 21, 2021
https://doi.org/10.18632/aging.202896How to Cite
Copyright: © 2021 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
M6A-related genes have been proven to play an important role in many cancers. However, the role of that in adrenocortical carcinoma (ACC) has not been fully elucidated. In the present study, 77 ACC samples from TCGA database were divided into localized (n = 46) and metastatic (n = 31) groups. Three differential expression genes (DEGs) and five prognostic m6A genes were screened out. M6A-related risk signature (RBM15 and HNRNPC) was constructed by the Lasso regression analysis. In TCGA cohort (training cohort), the risk signature was identified as an ACC-independent prognostic factor and can distinguish the prognostic difference of ACC patients with clinical stage I-II, T3-4 and N0 stages. A nomogram combining T stage and m6A risk score was constructed to predict the overall survival rate (OSR) of individual at 1,2,3 year. Meanwhile, its prognostic value was also confirmed in the validation cohort (GSE33371 dataset). The potential associations between m6A risk level and immune checkpoint inhibitors (ICIs) therapy were also investigated via the TISIDB online tool. High m6A risk not only can suppress immunotherapy-related biological processes, but also repress the expressions of immune-checkpoint markers. Moreover, five pairs of clinical specimens were collected to confirm the overexpression of HNRNPC and non-ectopic expression of RBM15 in tumor tissues. HNRNPC was proven to promote the proliferation, migration and invasion of H295R and SW13 cells through MTT and Transwell assays. In conclusion, the m6A-related risk signature was beneficial for prognostic analysis and can affect immune microenvironment in ACC. HNRNPC played a pro-cancer role in ACC progression.
Abbreviations
ACC: adrenocortical carcinoma; m6A: N6-methyladenosine; OS: overall survival; OSR: Overall survival rate; TCGA: The Cancer Genome Atlas; AML: Acute myeloid leukemia; IGF1R: Insulin-like growth factor 1 receptor; IFN: Interferon; VEGF: Vascular endothelial growth factor; PCA: Principal component analysis; EGFR: Epidermal growth factor receptor; DEGs: Differentially expressed genes; Lasso: least absolute shrinkage and selection operator; NK: Natural killer; GEPIA: Gene expression profiling interactive analysis; DCs: Dendritic cells; Perl: Practical Extraction and Report Language; Tregs: Regulatory T cells; t-SNE: t-distributed stochastic neighbor embedding; TCR: T-cell receptor; ssGSEA: Single-sample gene set enrichment analysis; NEPC: Neuroendocrine prostate cancer; dsRNA: double-stranded RNA; CRPC: Castration-resistant prostate cancer; CCR: Cytokine-cytokine receptor; APCs: Antigen-presenting cells; PD-L1: Programmed cell death 1 ligand 1; CTLA4: Cytotoxic T-lymphocyte associated protein 4; CD274: Cluster of differentiation 274; DCA: Decision curve analysis.