Abstract
Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-κB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) comprises 75–85% of newly diagnosed lung cancers
We further investigated the effect of miR-146a on cell growth, apoptosis and motility of human NSCLC cells
We found that the increased expression of miR-146a in the NSCLC cells resulted in the down-regulation of EGFR both at the mRNA and protein levels (Figure 10)
Summary
Non-small cell lung cancer (NSCLC) comprises 75–85% of newly diagnosed lung cancers. Over 70% of NSCLC patients present with advanced disease, and the overall 5-year survival rate for NSCLC is only 16%. For early-stage or locally advanced lung cancer, surgery is the most effective treatment, and combination chemotherapy is the standard adjuvant approach. For stage III/IV NSCLC, platinum-based combined chemotherapy is the current standard of care, but with much room for improvement [1,2]. The molecular mechanisms underlying the development of NSCLC are currently still poorly understood. A better understanding of these mechanisms will be helpful to develop novel therapeutic targets and strategies for the treatment of human NSCLC [3,4,5]
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