Up-regulation of miR-146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J

Abstract

BackgroundCisplatin (DDP)-based chemotherapy is the common first-line therapy for lung cancer. However, their efficacy is often limited by primary drug resistance and/or acquired drug resistance. The aim of this study was to investigate the function of miRNA-146a (miR-146a) in DDP-resistant non-small cell lung cancer (NSCLC), as well as the underlying mechanisms.MethodsThe effect of overexpression of miR-146a and/or knockdown of cyclin J (CCNJ) in A549/DDP and SPC-A1/DDP cells were investigated as follows. The cellular sensitivity to DDP, cell apoptosis, cell cycle and cell mobility were detected by CCK-8, flow cytometry, hoechst staining and cell invasion/migration assay, respectively. The effects of miR-146a overexpression in NSCLC resistant cells were further analyzed in a nude mouse xenograft model.ResultsOverexpression of miR-146a and/or knockdown of CCNJ significantly increased the sensitivity to DDP in A549/DDP and SPC-A1/DDP cells compared to NC group via arresting cell cycle, enhancing cell apoptosis, inhibiting cell viability and motility in vitro and in vivo. Furthermore, miR-146a could specially degrade the mRNA of CCNJ, as examined by dual luciferase report assay.ConclusionThe study indicates a crucial role of miR-146a in the development of acquired drug resistance to DDP in NSCLC cells. Further understanding of miR-146a mediated crosstalk networks may promote the clinical use of miR-146a analogue in NSCLC therapy.

Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy

“…The other miRNAs of this six miRNA panel had no significant differential changes. miR-146a-5p has been previously reported to be involved in the regulation of resensitization of cisplatin-resistant NSCLC cells (36). However, we failed to observe the impact of miR-146a-5p on the response to cisplatin through overexpression or silencing of miR-146a-5p in NSCLC cells, including PC-9, SPCA1, H1299, and H1975 (Supplementary Fig.…”

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…The authors attributed an oncogenic role of miR‐146a to targeting of DNA damage inducible transcript 3 (CHOP), a gene whose low expression is correlated with poor prognosis. Additionally, they suggested miR‐146a can promote NSCLC resistance to cisplatin (Tan et al, ), while two other publications showed the opposite (Shi et al, ; Yuwen et al, ). Overall, the conclusions made by Tan et al are questionable because multiple articles refute numerous aspects of their experimental results.…”

“…Clinically, patients with low miR‐146a expression in their lung tumors tended to have advanced stage cancer and metastases, while patients with high miR‐146a levels demonstrated longer progression‐free survival (Chen et al, ). Cell cycle progression is also slowed by miR‐146a, in part by specifically targeting cyclins D1/2 (Li et al, ) and cyclin J (Shi et al, ). These in vitro results were replicated in a xenograft mouse model, where implanted cells overexpressing miR‐146a formed smaller tumors (Li et al, ).…”

“…Shi et al found that restoration of miR‐146a expression in NSCLC cell lines increased sensitivity to cisplatin, as seen with cell cycle arrest, increased levels of apoptosis, inhibited cell viability, and slower rates of cell migration. The authors cited miR‐146a‐mediated regulation of cyclin J as a key player in these effects (Shi et al, ). Results shown by Yuwen and colleagues corroborated this work, though the main focus of their work was control of autophagy‐related protein 12 (ATG12) expression by miR‐146a (Yuwen et al, ).…”

A review of microRNAs related to the occurrence, diagnosis, and prognosis of non-small cell lung cancer

“…Yuwen et al [66] identified that serum exosomal miR-146a-5p might be a new biomarker for predicting the efficacy of DDP for NSCLC patients and real-time monitoring drug resistance. Shi et al [67] also investigated the role of miR-146a in the development of acquired drug resistance to DDP in NS-CLC cells, and found that overexpression of miR-146a significantly increased the sensitivity of NSCLC cells to DDP via blocking the cell cycle, enhancing cell apoptosis, and inhibiting cell viability and motility both in vitro and in vivo. Ma et al [68] reported that DLK1 was a potential target for miR-129-5p, and overexpression of miR-129-5p could inhibit NSCLC chemo-resistance to DDP through regulating DLK1.…”