Abstract
Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world due to its often delayed diagnosis. Identification of biomarkers with high sensitivity, specificity, and accessibility for early detection, such as circulating microRNAs, is therefore of utmost importance. In the present study, we identified a significantly higher expression of miR-146a-5p in the serum and tissue samples of NSCLC patients than that of the healthy controls. In parallel, miR-146a-5p was also highly expressed in three human NSCLC adenocarcinoma-cell lines (A549, H1299, and H1975) compared to the human bronchial epithelium cell line (HBE). By dual-luciferase reporter assay and manipulation of the expressions of miR-146a-5p and its target gene, tumor necrosis factor receptor-associated factor 6 (TRAF6), we showed that the functional effects of miR-146a-5p on NSCLC cell survival and migration were mediated by direct binding to and suppression of TRAF6. Overexpression of TRAF6 sufficiently reversed miR-146a-5p-induced cancer cell proliferation, migration, and apoptosis resistance. Our data implied that miR-146a-5p/TRAF6/NF-κB-p65 axis could be a promising diagnostic marker and a therapeutic target for NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and accounts for approximately 80–85% of all lung cancers
Measured by qRT-PCR, miR-146a-5p gene expression in NSCLC cancer tissues had a five-fold increase compared to the corresponding paracancerous tissues (Figure 1C), and was significantly overexpressed in three NSCLC cell lines (A549, H1299, and H1975) when compared with the human bronchial epithelium cell line (HBE; Figure 1D). miR-146a-5p was overexpressed in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) from TCGA database (Figure 1E)
By mining the three online miRNA target prediction databases, we found that tumor necrosis factor receptorassociated factor 6 (TRAF6) is one of the overlaps among all intersecting areas, suggesting it is a favorable target of miR-146a-5p
Summary
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and accounts for approximately 80–85% of all lung cancers. MicroRNAs (miRNAs) are a group of small non-coding RNA molecules of less than 25 nucleotides and present across species from plants, animals to some viruses (Di Leva et al, 2014). The miRNA-guided post-transcriptional control was mainly revealed in the immune system, the evidence is piling up to link it with a great number of other disorders, such as systemic lupus erythematosus (SLE) and common cancers in colon, stomach, ovary, cervical, prostate, and lung (Paik et al, 2011; Hung et al, 2013; Di Leva et al, 2014; Zheng et al, 2015; Polley et al, 2016; Jiang et al, 2017; Yin et al, 2017; Hu et al, 2018; Li et al, 2019). Similar to protein-coding genes, miRNAs can function as either oncogenes or tumor suppressors to be potential prognostic biomarkers (Thai et al, 2010; Jalava et al, 2012; Wang et al, 2016)
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