Modulation of NF-κB/miR-21/PTEN Pathway Sensitizes Non-Small Cell Lung Cancer to Cisplatin

Abstract

BackgroundPlatinum-based chemotherapy is a standard strategy for non-small cell lung cancer (NSCLC), while chemoresistance remains a major therapeutic challenge in current clinical practice. Our present study was aimed to determine whether inhibition of the NF-κB/miR-21/PTEN pathway could increase the sensitivity of NSCLC to cisplatin.MethodsThe expression of miR-21 in NSCLC tissues was determined using in situ hybridization. Next, the effect of miR-21 on the sensitivity of A549 cells to cisplatin was determined in vitro. Whether miR-21 regulated PTEN expression was assessed by luciferase assay. Furthermore, whether NF-κB targeted its binding elements in the miR-21 gene promoter was determined by luciferase and ChIP assay. Finally, we measured the cell viability and apoptosis under cisplatin treatment when NF-κB was inhibited.ResultsAn elevated level of miR-21 was observed in NSCLC lung tissues and was related to a short survival time. Exogenous miR-21 promoted cell survival when exposed to cisplatin, while miR-21 inhibition could reverse this process. The RNA and protein levels of PTEN were significantly decreased by exogenous miR-21, and the 3′-untranslated region of PTEN was shown to be a target of miR-21. The expression of miR-21 was regulated by NF-κB binding to its element in the promoter, a finding that was verified by luciferase and ChIP assay. Hence, inhibition of NF-κB by RNA silencing protects cells against cisplatin via decreasing miR-21 expression.ConclusionModulation of the NF-κB/miR-21/PTEN pathway in NSCLC showed that inhibition of this pathway may increase cisplatin sensitivity.

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

“…Yang et al demonstrate that NF‐κB up‐regulates the expression of miR‐21, by binding to its gene promoter 49. Other studies also document NF‐κB binding sites on the promoter of miR‐21 34, 50.…”

MicroRNA-21 Regulates Non-Small Cell Lung Cancer Cell Invasion and Chemo-Sensitivity through SMAD7

“…They have identified an inverse correlation between miR-21 and PTEN protein in tumor tissue and further showed that miR-21 post-transcriptionally down-regulates the expression of tumor suppressor PTEN and stimulates growth in NSCLC cells [40]. Later on, the regulatory axis of miR-21 and PTEN in NSCLC has been confirmed by follow-up studies [38,39,48,49,50]. Nevertheless, the regulation of SMAD7, and subsequently TGFβ receptor signaling, has not been reported before.…”

Emerging Role of MicroRNAs in mTOR Signaling

“…In particular, miR-21 targets multiple genes in mTOR pathway, including PTEN, p85α and PDCD4. Besides promoting malignant growth, the miR-21/PTEN/PI3K/AKT/mTOR axis has been shown to influence anti-cancer effects of zoledronic acid [80] , triptolide [81] , Metformin [82] , Matrine [83] and curcumin [84] , and modulate radiosensitivity [85, 86] and chemosensitivity to tamoxifen, fulvestrant [87] , sorafenib [88] , cisplatin [89, 90] , imatinib [91] , gefitinib [92] , doxorubicin [93] , daunorubicin [94] , anti-EGFR tyrosine kinase inhibitors (TKI) [95] and the CHOP chemotherapy regimen [96] . miR-21 also influences PI3K/AKT/mTOR signaling via PIK3R1 that negatively regulates p110 subunit under certain circumstances.…”