Abstract
BackgroundA growing body of evidence has demonstrated the vital roles of circular RNAs (circRNAs) in cancer progression and drug resistance. We intended to explore the roles and mechanisms of circ_ZFR in the paclitaxel (PTX) resistance and progression of non-small cell lung cancer (NSCLC).MethodsTwo NSCLC cell lines A549 and H460 were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to measure the levels of circ_ZFR, ZFR, miR-195-5p and karyopherin subunit alpha 4 (KPNA4) mRNA. RNase R assay was used to analyze the characteristic of circ_ZFR. MTT assay was carried out to assess PTX resistance and cell proliferation. Flow cytometry analysis was utilized to analyze cell cycle and apoptosis. Transwell assay was used to examine cell migration and invasion. Western blot assay was conducted to measure the protein levels of Ki67, Twist1, E-cadherin and KPNA4. Dual-luciferase reporter assay was adopted to verify the combination between miR-195-5p and circ_ZFR or KPNA4. Murine xenograft model assay was used to investigate the effect of circ_ZFR on PTX resistance of NSCLC in vivo.ResultsCirc_ZFR level was enhanced in PTX-resistant NSCLC tissues and cells. Knockdown of circ_ZFR suppressed PTX resistance, cell cycle process, proliferation, migration and invasion and induced apoptosis in PTX-resistant NSCLC cells. For mechanism analysis, circ_ZFR knockdown markedly downregulated the expression of KPNA4 by sponging miR-195-5p, thereby promoting PTX sensitivity and suppressing cell progression in PTX-resistant NSCLC cells. In addition, circ_ZFR silencing enhanced PTX sensitivity of NSCLC in vivo.ConclusionCirc_ZFR knockdown played a positive role in overcoming PTX resistance of NSCLC via regulating miR-195-5p/KPNA4 axis, which might provide a possible circRNA-targeted therapy for NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is the major type of lung cancer with an occupancy case rate of more than 80% [1, 2]
Our results showed that PTX resistance was produced in A549/PTX and H460/PTX cells, as demonstrated by the elevated IC50 value of PTX in A549/ PTX and H460/PTX cells (Fig. 1c)
The results showed that circ_ZFR was resistant to RNase R digestion, while linear ZFR was markedly decreased following the treatment of RNase R (Fig. 1d, e)
Summary
Non-small cell lung cancer (NSCLC) is the major type of lung cancer with an occupancy case rate of more than 80% [1, 2]. The treatment strategies for NSCLC include surgery, radiotherapy, chemotherapy and immunotherapy [4]. Paclitaxel (PTX) is an antineoplastic drug in various types of tumors, including NSCLC [5]. It is crucial to discover new methods to overcome the resistance of NSCLC patients to PTX. A growing body of evidence has demonstrated the vital roles of circular RNAs (circRNAs) in cancer progression and drug resistance. We intended to explore the roles and mechanisms of circ_ZFR in the paclitaxel (PTX) resistance and progression of non-small cell lung cancer (NSCLC)
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