m6A 调控基因在非小细胞肺癌中的病理组织表达模式及临床意义。

The pathological tissue expression pattern and clinical significance of m6A-regulatory genes in non-small cell lung cancer.

机构信息

Department of Pulmonary and Critical Care Medicine, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China.

Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

出版信息

J Gene Med. 2022 Feb;24(2):e3397. doi: 10.1002/jgm.3397. Epub 2021 Dec 1.

DOI:10.1002/jgm.3397

PMID:34751492

Abstract

BACKGROUND

Aberrant expression of m6A-related proteins contributes to the occurrence and progression of non-small cell lung cancer (NSCLC). Current studies mainly focus on single m6A regulatory genes and their underlying mechanisms, and the expression of multiple m6A regulatory proteins in NSCLC remains unclear. Therefore, it is necessary to systematically examine these proteins, particularly in clinical specimens.

METHODS

Bioinformatic analysis was used to determine the expression of m6A regulatory genes and their correlation with common gene mutations, such as TP53, EGFR and KRAS, using The Cancer Genome Atlas (TCGA) and the AE-meta databases. Immunohistochemistry was employed to analyze the protein expression of m6A regulatory proteins in 61 benign lung tissues and 316 NSCLC tissues. Statistical analysis was performed to calculate the correlation between the expression of m6A regulatory proteins and clinicopathological features, survival, and common gene mutations in lung carcinoma patients.

RESULTS

Analysis of the mRNA levels of 13 core m6A regulators, using information from TCGA and the AE-meta databases, revealed that YTHDF1 levels were upregulated in NSCLC compared to those in adjacent normal tissues. Immunohistochemical staining showed that the expression of METTL3, ALKBH5, YTHDC2 and YTHDF1 was significantly upregulated in NSCLC tissues. Further analyses demonstrated a positive correlation between differentially expressed m6A regulatory proteins, including METTL3, ALKBH5, YTHDC2 and YTHDF1, and the poor clinicopathological features and survival of NSCLC patients. According to the statistics of NSCLC patients enrolled in the present study, the protein levels of METTL3 in patients with EGFR exon-19 mutation were higher than those in patients with wild-type EGFR.

CONCLUSIONS

Our results indicate that m6A regulators, including METTL3, ALKBH5, YTHDC2 and YTHDF1, could serve as predictive markers of NSCLC, which will facilitate the early detection and diagnosis of NSCLC.

摘要

背景

m6A 相关蛋白的异常表达导致非小细胞肺癌（NSCLC）的发生和进展。目前的研究主要集中在单个 m6A 调控基因及其潜在机制上，而 NSCLC 中多种 m6A 调控蛋白的表达尚不清楚。因此，有必要系统地研究这些蛋白，特别是在临床标本中。

方法

使用 The Cancer Genome Atlas（TCGA）和 AE-meta 数据库进行生物信息学分析，确定 m6A 调控基因的表达及其与常见基因突变（如 TP53、EGFR 和 KRAS）的相关性。采用免疫组织化学法分析 61 例良性肺组织和 316 例 NSCLC 组织中 m6A 调控蛋白的蛋白表达。统计分析计算 m6A 调控蛋白表达与肺癌患者临床病理特征、生存和常见基因突变的相关性。

结果

利用 TCGA 和 AE-meta 数据库的信息分析 13 个核心 m6A 调控因子的 mRNA 水平，结果显示 YTHDF1 在 NSCLC 中的表达高于其在相邻正常组织中的表达。免疫组织化学染色显示，METTL3、ALKBH5、YTHDC2 和 YTHDF1 在 NSCLC 组织中的表达明显上调。进一步分析表明，差异表达的 m6A 调控蛋白，包括 METTL3、ALKBH5、YTHDC2 和 YTHDF1，与 NSCLC 患者不良的临床病理特征和生存呈正相关。根据本研究纳入的 NSCLC 患者的统计数据，EGFR 外显子 19 突变患者的 METTL3 蛋白水平高于 EGFR 野生型患者。