Abstract
Background/Aim: The role of long non-coding RNA (lncRNA) and competing endogenous RNAs (ceRNA) networks in bladder cancer, especially the function of lncRNA-miRNA-mRNA regulatory network in bladder cancer, are still relatively poorly understood. This research mainly used transcriptome sequencing to screen key lncRNAs and ceRNAs, explore their pathogenic mechanism in bladder cancer, and search for potential diagnostic and therapeutic targets. Methods: High-throughput transcriptome sequencing, combined with the limma package, Kaplan-Meier curve analysis, lncRNA-mRNA coexpression network, univariate Cox analysis, multivariate Cox analysis, protein-protein interaction (PPI), functional enrichment, weighed gene co-expression network analysis (WGCNA), ceRNA network and quantitative PCR (qPCR) analyses were performed to assess and screen differentially expressed lncRNAs and mRNAs. Then, the effects of MIR100HG on the proliferation, migration and invasion of the bladder cancer cell line 5,637 were evaluated using cell counting kit-8(CCK-8), wound-healing and transwell assays, respectively. A dual luciferase reporter assay was used to validate the MIR100HG/miR-142-5p and miR-142-5p/CALD1 targeting relationship, and the regulatory relationship among MIR100HG/miR-142-5p/CALD1 expression was explored using qPCR and western blot. Results: A total of 127 differentially expressed lncRNAs and 620 differentially expressed mRNAs were screened. Based on the survival prognosis analysis, Cox analysis, lncRNA-mRNA network, PPI network and WGCNA, we obtained 3 key lncRNAs and 13 key mRNAs, as well as the MIR100HG/miR-142-5p/CALD1 key regulatory axis. qPCR results showed that compared with the adjacent tissues, the expression of MIR100HG and CALD1 was up-regulated, and the expression of miR-142-5p was down-regulated. Moreover, MIR100HG expression was positively correlated with the tumor grade and clinical grade of patients with bladder cancer. Overexpression of MIR100HG effectively promoted the proliferation, migration and invasion of 5,637 cells, inhibited the expression of miR-142-5p, and induced the expression of CALD1 in 5,637 cells. In addition, miR-142-5p inhibited CALD1 expression in bladder cancer cells through a direct association, and reversed the proliferation and CALD1 expression in 5,637 cells overexpressing of MIR100HG. Conclusion: MIR100HG regulates CALD1 expression by targeting miR-142-5p to inhibit the proliferation, migration and invasion of bladder cancer cells. MIR100HG is an independent prognostic factor for bladder cancer, with potential as a biomarker for the diagnosis and treatment of bladder cancer.
Highlights
Bladder cancer is a malignant tumor with high prevalence and high mortality rates
RT-qPCR and western blot results showed CALD1 expression was significantly increased by pCDH-MIR100HG and reversed by the miR-142-5p mimic (Figures 9F,G). These results further revealed the direct targeting relationship among miR-142-5p, MIR100HG and CALD1, and suggested that the MIR100HG/miR-142-5p/ CALD1 is involved in the progression of bladder cancer
The lncRNA MIR100HG was significantly up-regulated in bladder cancer tissues compared with adjacent tissues, and its high expression was positively correlated with the histological grade and clinical stage of bladder cancer
Summary
Bladder cancer is a malignant tumor with high prevalence and high mortality rates. Approximately 400,000 new patients are diagnosed with bladder cancer worldwide each year, especially men, and one-third of them will die (Lenis et al, 2020; Richters et al, 2020; Teoh et al, 2020). As mentioned above, ceRNAs are a classic regulatory mechanism of lncRNAs that regulate the expression and activity of mRNAs through targeted binding to noncoding RNAs (such as miRNAs). According to Chen et al, the lncRNA MST1P2 targets the miR-133b axis to regulate the Sirt1/ p53 signaling pathway and affect the chemotherapy resistance of bladder cancer to cisplatin (Chen et al, 2020a). Does this classic regulatory mechanism exist in bladder cancer? Does this classic regulatory mechanism exist in bladder cancer? A screen of newer key lncRNAs and analysis of their possible regulatory mechanisms is necessary to better understand the mechanisms underlying the carcinogenesis and exacerbation of bladder cancer
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