Abstract
This study aims to use bioinformatics methods to determine the epigenetic changes in microRNA expression and DNA methylation caused by cigarette smoking. The data of mRNA, miRNA expression, and methylation microarray were obtained from the GEO database to filter differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and methylated CpG probes (DMPs) through the limma package. The R clusterProfile package was used for functional annotation and enrichment analysis. The protein-protein interaction (PPI) network was constructed by the String database and visualized in Cytoscape software. Starbase database was employed to predict lncRNA and CirRNA based on the sequence of miRNA, and to establish a regulatory network of ceRNA. By overlapping DEG and DEM, 107 down-miRNA-targeted up-regulated genes and 65 up-miRNA-target down-regulated genes were obtained, which were mainly enriched in autophagy signaling pathways and protein ubiquitination pathways, respectively. In addition, 324 genes with low methylation and high expression and 204 genes with high methylation and low expression were respectively related to the degeneration of the nervous system and the function of the cardiovascular system. Interestingly, 43 genes were up-regulated under the dual regulation of reduced miRNA and hypomethylation, while 14 genes were down-regulated under the dual regulation of increased miRNA and hypermethylation. Ten chemicals have been identified as putative therapeutic agents for pathological conditions caused by smoking. In addition, among these genes, HSPA4, GRB2, PRKCA, and BCL2L1 could play a fundamental role in related diseases caused by smoking and may be used as the biomarkers for precise diagnosis and targets for future therapies of smoking-related diseases.
Highlights
Smoking can cause a variety of tumors and non-tumor diseases
Pivotal genes and pathways responsible for key events in epigenetic changes regulated by microRNA binding and DNA methylation have been identified in the present study
The Mechanistic Target of Rapamycin (mTOR) signal pathway can be activated by various external factors such as growth factors, stress, oxygen, and amino acid, and is involved in many physiological processes, such as liposome synthesis, energy metabolism, and autophagy
Summary
Smoking can cause a variety of tumors and non-tumor diseases. It is estimated that 40% of human cancers are smoking-related which are responsible for more than 5 million preventable deaths worldwide per year (Ambrose and Barua, 2004). It has been reported that there are more than 69 harmful components, including 10 kinds of polycyclic aromatic hydrocarbons, 10 kinds of nitrosamines, eight kinds of heterocyclic amines, and six kinds of heterocyclic hydrocarbons generated when smoking (Benowitz, 2003). It does not directly cause certain diseases. The pathogenesis caused by cigarette smoking includes inflammation and immune suppression, reactive oxidative species generation, and apoptosis (Yoon et al, 2021). The exact mechanism leading to smoking-related diseases and deaths remains largely unknown. L.; Zhang et al, 2019)
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