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Lncrna APCDD1L-AS1 Induces Icotinib Resistance by Inhibition Of

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Lncrna APCDD1L-AS1 Induces Icotinib Resistance by Inhibition Of Wu et al. Biomarker Research (2021) 9:9 https://doi.org/10.1186/s40364-021-00262-3 RESEARCH Open Access LncRNA APCDD1L-AS1 induces icotinib resistance by inhibition of EGFR autophagic degradation via the miR-1322/miR-1972/ miR-324-3p-SIRT5 axis in lung adenocarcinoma Jie Wu1,2†, Chunlei Zheng3,4,5†, Yizhe Wang1, Zichang Yang3,4,5,CeLi3,4,5, Wanxia Fang3,4,5, Yue Jin3,4,5, Kezuo Hou3,4,5, Yang Cheng1, Jianfei Qi6, Xiujuan Qu3,4,5, Yunpeng Liu3,4,5, Xiaofang Che3,4,5* and Xuejun Hu1* Abstract Background: Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer. Methods: Molecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance. Results: A novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib- resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/ miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib. (Continued on next page) * Correspondence: [email protected]; [email protected] †Jie Wu and Chunlei Zheng contributed equally to this work. 1Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, No.155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning, China 3Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang 110001, Liaoning, China Full list of author information is available at the end of the article © The Author(s). 2021, corrected publication April 2021. Open Access 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wu et al. Biomarker Research (2021) 9:9 Page 2 of 17 (Continued from previous page) Conclusion: APCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients. Keywords: LncRNA APCDD1L-AS1, Lung adenocarcinoma, Icotinib-resistance, Autophagy, SIRT5 Background pivotal role in conferring anticancer drug resistance [16, Lung cancer is one of the most common malignancies 17]. LncRNA GSTM3TV2 could promote gemcitabine and the leading cause of cancer-related deaths world- resistance by sponging let-7 with concomitant upregula- wide [1, 2]. In the past ten years, the development of tar- tion of LAT2 and OLR1 in pancreatic cancer [18]; geted therapy has greatly improved the survival of lung LncRNAH19 induced autophagy and this could contrib- cancer patients, especially those with lung adenocarcin- ute to tamoxifen resistance via H19/SAHH/DNMT3B oma (LUAD). Approximately 40% of LUAD patients in axis in breast cancer [19]; MALAT1 contributed to gefi- Asian carry the sensitive mutations in epidermal growth tinib resistance by sponging miR-200a and enhancing factor receptor (EGFR)[3]. EGFR-TKIs, such as gefitinib, ZEB1 expression [20]. However, the studies about erlotinib and icotinib, have been recommended world- EGFR-TKI resistance related lncRNAs are still limited, wide as a standard first-line regimen. However, since the and their functional mechanisms remain largely majority of the patients acquired drug resistance after unknown. initial response to EGFR-TKIs within 10–16 months [4], In the current study, we identified a novel icotinib EGFR-TKIs resistance has become a major obstacle in resistance-related lncRNA, APCDD1L-AS1, and found the treatment of LUAD. The EGFR (T790M) mutation that APCDD1L-AS1 could upregulateSIRT5 expression and gene amplification of MET are known to be the by sponging with miR-1322/miR-1972/miR-324-3pin main molecular mechanisms of resistance to EGFR- LUAD cells. SIRT5 inhibited autophagic degradation of TKIs, whereas the third-generation EGFR-TKIs (Osimer- EGFR to induce icotinib resistance. An autophagy initi- tinib) or the combination of MET inhibitors (crizotinib) ator could perfectly reverse icotinib resistance in LUAD are wildly used for the therapy of these patients [5]. We cells. Therefore, this study revealed a novel lncRNA- and others have reported that the PI3K-AKT-mTOR or mediated mechanism of icotinib resistance, and provided STAT3 signaling pathway also contributes to EGFR- a potential strategy for overcoming icotinib resistance in TKIs resistance, and the mTOR or STAT3 inhibition LUAD patients. could partially reverse this phenomenon [6–9]. In addition, we recently reported that Grb2 was highly expressed in icotinib-resistant LUAD cells, whereas and Methods the combination of Grb2 inhibitor lymecycline could en- Establishment of icotinib-resistant cells and cell culture hance the sensitivity to icotinib [6]. However, a large Human lung adenocarcinoma cell lines (PC9, HCC827) number of patients still have no effective strategy for were purchased from American type culture collection overcoming EGFR-TKI resistance [10]. Therefore, it is (Manassas, VA, USA). The icotinib (Betta Pharmaceuti- urgent to further explore the mechanism of EGFR-TKIs cals Co., Ltd., China) resistant lung adenocarcinoma resistance, and develop more effective therapeutic strat- cells PC9/IcoRL (low-dose icotinib-resistant), PC9/ egies in the treatment of LUAD. IcoRH (high-dose icotinib-resistant), HCC827/IcoRL With the development of next generation sequencing and HCC827/IcoRH, without T790M mutation and technologies, it has been well known that only < 2% of MET amplification confirmed by sequencing, were the human transcriptional products encode proteins, established with a gradient concentration of icotinib – μ whereas the remaining 98% are non-coding RNAs (0.01 20 M) for over 6 months. All the cells were main- (ncRNAs) lacking protein-coding potential [11]. Long tained in RPMI-1640 medium (Gibco, Waltham, MA, non-coding RNAs (lncRNAs) are a novel class of USA) supplemented with 10% fetal bovine serum ncRNAs with more than 200 nucleotides in length [12– (HyClone, GE Healthcare LifeSciences, Logan, UT, USA) 14]. LncRNAs are known to be involved in various cellu- and were cultured in a humidified incubator at 37 °C lar processes such as cell differentiation, autophagy and with 5% CO2. The autophagy inhibitor chloroquine apoptosis [15]. To date, numerous lncRNAs are recog- (CQ) and 3-Methyladenine (3-MA) were purchased from nized as novel biomarkers and therapeutic targets in the Sigma-Aldrich, St. Louis, MO, USA and Selleck Chemi- diagnosis and treatment of malignancies. Furthermore, cals, Houston, TX, USA, respectively. The autophagy ini- mounting studies demonstrated that lncRNAs play a tiator, rapamycin, was purchased from Sigma-Aldrich, USA. The protein synthesis inhibitor cycloheximide Wu et al. Biomarker Research (2021) 9:9 Page 3 of 17 (CHX) and the proteasome inhibitor MG-132were pur- using MTT assay. All experiments were performed in chased from Sigma-Aldrich, USA. triplicate. RNA extraction and qRT-PCR Colony formation Total RNA was purified using Trizol reagent (Invitrogen, Cells were seeded into 12-well plate (600 cells/well) in Carlsbad, CA, USA). PARIS™ Kit (Invitrogen, AM1921) standard medium. Next day, different concentrations of ico- was utilized to isolate nuclear and cytoplasmic RNA ac- tinib were added into the medium. Two weeks later, live cording to the manufacturer’s instructions. RNA was cells were stained
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