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Lncrna FOXD3-AS1 Promoted Chemo-Resistance of NSCLC Cells

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Lncrna FOXD3-AS1 Promoted Chemo-Resistance of NSCLC Cells Zeng et al. Cancer Cell Int (2020) 20:350 https://doi.org/10.1186/s12935-020-01402-9 Cancer Cell International PRIMARY RESEARCH Open Access LncRNA FOXD3-AS1 promoted chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis Zhaolong Zeng1,2†, Guofang Zhao1,2†, Huangkai Zhu3†, Liangqin Nie4, Lifeng He1, Jiangtao Liu5, Rui Li1, Shuai Xiao1 and Gang Hua1* Abstract Background: This study aims to investigate the mechanism underlying the high level of long non-coding RNA FOXD3-AS1 in cisplatin-resistant NSCLC cells. Methods: Cisplatin-resistant cells were generated from A549 cells. CCK-8 were used to evaluate cell proliferation. The FOXD3-AS1, miR-127-3p, MDM2 and MRP1 mRNA expression levels were confrmed by qRT-PCR. Protein levels of MDM2 and MRP1 were determined by western blot assay. Luciferase reporter and RNA pull-down assays were evalu- ated the relationship between miR-127-3p and FOXD3-AS1/MDM2. In vivo tumor growth was evaluated in a xeno- graft nude mice model. Results: FOXD3-AS1 was up-regulated in cisplatin-resistant NSCLC cells (A549/DDP and H1299/DDP cells) in com- parison with their parental cell lines. Overexpression of FOXD3-AS1 promoted cisplatin-resistance in A549 and H1299 cells; while FOXD3-AS1 knockdown sensitized A549/DDP and H1299/DDP cells to cisplatin treatment. FOXD3-AS1 reg- ulated miR-127-3p expression by acting as a competing endogenous RNA, and miR-127-3p repressed MDM2 expres- sion via targeting the 3′UTR. MiR-127-3p overexpression and MDM2 knockdown both increased the chemo-sensitivity in A549/DDP cells; while miR-127-3p knockdown and MDM2 overexpression both promoted chemoresistance in A549 cells. Further rescue experiments revealed that miR-127-3p knockdown or MDM2 overexpression counteracted the suppressive efects of FOXD3-AS1 knockdown on chemo-resistance and MRP1 expression in A549/DDP cells. In vivo studies showed that FOXD3-AS1 knockdown potentiated the antitumor efects of cisplatin treatment. Inspec- tion of clinical samples showed the upregulation of FOXD3-AS1 and MDM2, and down-regulation of miR-127-3p in NSCLC tissues compared to normal adjacent tissues. Conclusion: In conclusion, our results suggest that LncRNA FOXD3-AS1 promotes chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis. Our fndings may provide novel perspectives for the treatment of NSCLC in patients resistant to chemotherapy. Keywords: Chemo-resistance, NSCLC, FOXD3-AS1, miR-127-3p, MDM2, Cisplatin Background *Correspondence: [email protected] Lung cancer represents one of the most deadly tumor †Zhaolong Zeng, Guofang Zhao and Huangkai Zhu contributed equally to this work malignancies with patients having very low overall sur- 1 Department of Thoracic Surgery, Hwamei Hospital, University of Chinese vival rate, due to the high metastasis of this disease [1, Academy of Sciences, No. 41 Northwest Street, Haishu District, Ningbo 2]. Non-small cell lung cancer (NSCLC) is the main City 315000, Zhejiang Province, China Full list of author information is available at the end of the article type of lung and accounts for more than 80% of all the © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zeng et al. Cancer Cell Int (2020) 20:350 Page 2 of 12 lung cancer cases [3, 4]. Chemotherapy and surgical Materials and methods resection are the main strategies for treating NSCLC, Collection of clinical samples and cisplatin-based chemotherapy has been widely Te procedures for collecting patients’ lung tissue used in treating NSCLC [3]. However, the development samples were approved by the Ethics Committee of of cisplatin resistance has been a major obstacle in Hwamei Hospital, and the written informed consent treating NSCLC [5, 6]. Unfortunately, the factors that was signed by each patient. Te lung cancer tissues contribute to cisplatin resistance in NSCLC have not and normal adjacent lung tissues were collected from been fully understood yet. Hence, exploration of novel 40 NSCLC patients who received surgical resection at strategies to promote cisplatin sensitivity is urgent for Hwamei Hospital between March 2015 and November us to have a better control of this malignancy. 2017. All the patients had no chemo-/radio-therapy Long non-coding RNAs (lncRNAs) belong to a class before the surgery. Te collected tissue samples were of non-coding RNAs with > 200 nucleotides in length, immediately frozen in liquid nitrogen and stored at and various biological functions of lncRNAs such as − 80 °C for future use. cell proliferation, cell apoptosis, cell diferentiation have been identifed [7, 8]. Emerging evidence has Cell lines and culture emphasized the vital roles of lncRNAs in the regula- Normal human lung bronchial epithelial cells (NHBE) tion of cisplatin resistance in NSCLC. For examples, and NSCLC cell lines (A549 and H1299) were purchased lncRNA colon cancer associated transcript 1 (CCAT1) from the ATCC (Manassas, USA). Te NHBE, A549 was up-regulated in cisplatin-resistant NSCLC cells, and H1299 cells were cultured in DMEM (Gibco, Grand and CCAT1 regulated SRY-Box 4 expression to pro- Island, USA) supplemented with 10% fetal bovine serum mote cisplatin resistance in NSCLC cells [9]. LncRNA (FBS; Invitrogen, Carlsbad, USA), 100 mg/ml strepto- bladder cancer associated transcript 1 (BLCAT1) was mycin and 100 U/ml penicillin in a humidifed air at up-regulated in NSCLC cells and BLACAT1 overex- 37 °C with 5% CO2. To establish cisplatin-resistant A549 pression contributed to NSCLC cisplatin resistance via (A549/DDP) and H1299 cells (H1299/DDP), A549 and modulating autophagy [10]. LncRNA EGFR antisense H1299 cells were frst treated with 0.1 mg/ml cisplatin RNA 1 (EGFR-AS1) was found to be elevated in plasma (Tocris Bioscience, Minneapolis, USA) and then gradu- of NSCLC patients and EGFR-AS1 overexpression pro- ally exposed to cisplatin with step-wise increased con- moted cisplatin resistance in NSCLC [11]. Recent evi- centrations till 1 mg/ml. Te established A549/DDP and dence implied that lncRNA FOXD3 antisense RNA1 H1299/DDP cells were cultured in full medium contain- (FOXD3-AS1) was involved in the progression of dif- ing 1 mg/ml until further use. ferent malignancies [12–15]. Unfortunately, little is known about FOXD3-AS1 regarding chemo-resistance Cell transfections with plasmids, miRNAs and small in NSCLC. interfering (siRNAs) One of the main functions of lncRNA is known to act Te control vector (pcDNA3.1) and the vector for over- as a competing endogenous RNA (ceRNA) to infuence expressing FOXD3-AS1 (pcDNA3.1-FOXD3-AS1) or microRNAs (miRNAs) expression [16]. MiRNAs belong murine double minute 2 (MDM2; pcDNA3.1-MDM2) to a class of small non-coding RNAs with 21–23 nucle- were purchased from GenePharma (Shanghai, China). otides in length and play pivotal roles in regulating Te mimics and inhibitors for miR-127-3p and the neg- cellular functions [16–18]. Tere is existing evidence ative controls were purchased from Ribobio (Guang- showing that miR-127-3p acts as a tumor suppressor in zhou, China). Te siRNAs for targeting FOXD3-AS1 various types of cancers including ovarian cancer [19], (si-FOXD3-AS1) or MDM2 (si-MDM2), and the respec- osteosarcoma [20], glioblastoma [21] and oral squa- tive scrambled negative controls were designed and syn- mous cell carcinoma [22]. Up to date, the role of miR- thesized by Ribobio. All the relevant oligonucleotides 127-3p in NSCLC progression and chemo-resistance sequences were shown in Additional fle 1: Table S1. All has not been explored yet. the plasmids, miRNA and siRNA oligonucleotides were In this study, we analyzed the FOXD3-AS1 in cispl- transfected into NSCLC cells using Lipofectamine 2000 atin-resistant NSCLC cell lines (A549/DDP and H1229/ reagent (Invitrogen). Te time point for harvesting the DDP cells) and explored the underlying mechanisms transfected cells was at 48 h post-transfection. of FOXD3-AS1 in regulating cisplatin resistance in A549/DDP and H1229/DDP cells. Tis study may pro- Cisplatin treatment and cell counting kit‑8 (CCK‑8) assay vide novel perspectives for the treatment of NSCLC in Te transfected NSCLC cells were seeded onto the patients resistant to chemotherapy. 96-well plates. Following an incubation of 24 h, cells Zeng et al. Cancer Cell Int (2020) 20:350 Page 3 of 12 were incubated with diferent concentrations (0, 3, 10, Technology, Danvers, USA), MRP1 (1:1500; Cell Signal- 30, 100 and 300 μM) of cisplatin for 48 h. After cispl- ing Technology) and β-actin (1:2000; Cell Signaling Tech- atin treatment, the NSCLC cells were further incubated nology). After a further washing with TBST, membranes with CCK-8 solution as per manufacturer’s protocol for were again incubated with horseradish peroxidase-conju- 1 h at 37 °C. Cell viability of the transfected cells were gated secondary antibodies (1:2500; Cell Signaling Tech- determined by measuring the absorbance at 450 nm.
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