Abstract
Objective: The aim of this study was to investigate the molecular mechanisms underlying cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC) cells by constructing a competing endogenous RNA (ceRNA) network.Methods: The gene expression profiles of human lung adenocarcinoma DDP-resistant cell line (A549/DDP) and its progenitor (A549) were comparatively evaluated by whole-transcriptome sequencing. The differentially expressed genes (DEGs) were subjected to KEGG pathway analysis. The expression levels of mRNAs involved in several pathways associated with conferring DDP resistance to tumor cells were evaluated. The ceRNA network was constructed based on the mRNA expression levels and the sequencing data of miRNA and lncRNA. Several ceRNA regulatory relationships were validated.Results: We quantified the expression of 17 genes involved in the six pathways by quantitative real-time polymerase chain reaction (qRT-PCR). The differential protein expression levels of eight genes were quantified by western blotting. Western blot analysis revealed six differentially expressed proteins (MGST1, MGST3, ABCG2, FXYD2, ALDH3A1, and GST-ω1). Among the genes encoding these six proteins, ABCG2, ALDH3A1, MGST3, and FXYD2 exhibited interaction with 8 lncRNAs and 4 miRNAs in the ceRNA regulatory network. The expression levels of these lncRNAs and miRNAs were quantified in cells; among these, 6 lncRNAs and 4 miRNAs exhibited differential expression between A549/DDP and A549 groups, which were used to construct a ceRNA network. The ceRNA regulatory network of MSTRG51053.2-miR-432-5p-MGST3 was validated by luciferase reporter assay.Conclusion: The MSTRG51053.2 lncRNA may function as a ceRNA for miR-432-5p to regulate the DDP resistance in NSCLC. The MGST1, MGST3, GST-ω1, and ABCG2 mRNAs, miR-432-5p and miR-665 miRNAs, and MSTRG51053.2 and PPAN lncRNAs can serve as potential DDP drug targets to reverse DDP resistance in NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related deaths [1]
A total of 882 downregulated and 554 upregulated mRNAs, 219 downregulated and 273 upregulated lncRNAs, 106 downregulated, and 17 upregulated circRNAs, as well as 89 downregulated and 15 upregulated miRNAs were identified between A549/DDP and A549 groups
We focused on 6 pathways that are associated with conferring DDP resistance to tumor cells, including bile secretion, metabolism of xenobiotics by cytochrome P450, glutathione metabolism, drug metabolism-cytochrome P450, platinum drug resistance, and chemical carcinogenesis
Summary
Lung cancer is the leading cause of cancer-related deaths [1]. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases [2]. Most of the patients with NSCLC are diagnosed at advanced stage and exhibit a 5-year survival rate of only 17.4% [1, 2]. The first line of treatment for patients with NSCLC, especially advanced stage cases, is cisplatin (DDP)-based chemotherapy [3, 4]. DDP exhibits cytotoxicity by interacting with the DNA to form platinum-DNA adducts, which inhibit DNA replication [5, 6]. Tumors exhibit resistance to DDP chemotherapy, which is a major impediment to successful chemotherapy. The mechanism underlying tumor resistance to DDP is complex. There is an urgent need to elucidate this mechanism
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