Abstract
Abnormal methylation of N6 adenosine (m6A) in RNA plays a crucial role in the pathogenesis of many types of tumors. However, little is known about m6A RNA methylation in lung adenocarcinoma. This study aimed to identify the value of m6A RNA methylation regulators in the malignant progression and clinical prognosis of lung adenocarcinoma. The RNA-seq transcriptome data and corresponding clinical information of lung adenocarcinoma were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Then the identification of differentially expressed m6A RNA methylation regulators between cancer samples and normal control samples, different subgroups by consensus expression of these regulators and the prognostic signature were achieved using R software with multiple corresponding packages. The results showed that the expression levels of HNRNPC, YTHDF1, KIAA1429, RBM15, YTHDF2, and METTL3 in cancer group were significantly up-regulated (P < 0.05), while expression levels of FTO, ZC3H13, METTL14, YTHDC1 and WTAP in cancer group were significantly down-regulated (P < 0.05) compared with control group. Two subgroups identified by consensus expression of these regulators were closely related to the clinicopathological features, clinical outcomes and malignancy of lung adenocarcinoma. In addition, a 3-gene risk signature including KIAA1429, RBM15, and HNRNPC was constructed and the lung adenocarcinoma patients in TCGA database were divided into high-risk group and low-risk group based on the median risk score. In conclusion, the prognostic signature-based risk score calculated according to the expression levels of KIAA1429, RBM15, and HNRNPC, was not only strongly associated with clinical outcomes and clinicopathological features, but also an independent prognostic factor in lung adenocarcinoma.
Highlights
Lung adenocarcinoma is an aggressive disease which derives from small airway epithelial or type II alveolar cells, accounting for approximately 40% of all lung cancer cases as the most common type (Noguchi et al, 1995; Zappa and Mousa, 2016)
The lung adenocarcinoma patients in The Cancer Genome Atlas (TCGA) database were divided into high-risk group and low-risk group based on the median risk score
Considerable effort should be made to prevent disease progression due to eventual acquired resistance of almost all targeted therapies (Ke et al, 2018; Wu and Shih, 2018; Yoneshima et al, 2018). Methylation of N6 adenosine (m6A) RNA methylation, which is shown essential for better prediction of malignant behavior and clinical prognosis of many cancers, has drawn attention in the exploration of earlier diagnosis and more effective treatment of lung adenocarcinoma (Taketo et al, 2018; Hu et al, 2019; Zou et al, 2019)
Summary
Lung adenocarcinoma is an aggressive disease which derives from small airway epithelial or type II alveolar cells, accounting for approximately 40% of all lung cancer cases as the most common type (Noguchi et al, 1995; Zappa and Mousa, 2016). The evolution of lung adenocarcinoma is a multistep process which involves genetic, epigenetic and environmental factor interactions, resulting in the dysregulation of key oncogenes as well as tumor suppressor genes and subsequent activation of cancer-related signaling pathways (Ansari et al, 2016). Alternative therapeutic strategies for treating lung adenocarcinoma underscore their importance due to the absence of target gene mutation in a significant proportion of lung adenocarcinoma and the resistance of new targeted drugs (Minguet et al, 2016). Among these strategies, epigenetics, especially RNA methylation has drawn wide attention (Chao et al, 2020). “Writers,” including METTL3, METTL14, KIAA1429, WTAP, RBM15, and ZC3H13, mediate the process of methylation modification of RNA; “erasers,” such as FTO and ALKBH5, remove the RNA methylation modification signal; “readers,” consist of YTHDC1, YTHDC2, YTHDF1, YTHDF2, and HNRNPC, recognize those m6A-modified RNAs to regulate the expression of various genes (Tong et al, 2018)
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