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IRF1 Negatively Regulates Oncogenic KPNA2 Expression Under Growth Stimulation and Hypoxia in Lung Cancer Cells

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IRF1 Negatively Regulates Oncogenic KPNA2 Expression Under Growth Stimulation and Hypoxia in Lung Cancer Cells OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH IRF1 Negatively Regulates Oncogenic KPNA2 Expression Under Growth Stimulation and Hypoxia in Lung Cancer Cells This article was published in the following Dove Press journal: OncoTargets and Therapy Jie-Xin Huang1 Purpose: Karyopherin alpha 2 (KPNA2) has been reported as an oncogenic protein in Yi-Cheng Wu2 numerous human cancers and is currently considered a potential therapeutic target. However, Ya-Yun Cheng 1 the transcriptional regulation and physiological conditions underlying KPNA2 expression Chih-Liang Wang3,4,* remain unclear. The aim of the present study was to investigate the role and regulation of – Chia-Jung Yu 1,4 6,* interferon regulatory factor-1 (IRF1) in modulating KPNA2 expression in lung adenocarci- noma (ADC). 1 Graduate Institute of Biomedical Materials and methods: Bioinformatics tools and chromatin immunoprecipitation were Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; used to analyze the transcription factor (TF) binding sites in the KPNA2 promoter region. We 2Department of Thoracic Surgery, Chang searched for a potential role of IRF1 in non-small-cell lung cancer (NSCLC) using Gung Memorial Hospital, Taoyuan, Oncomine and Kaplan-Meier Plotter datasets. qRT-PCR was applied to examine the role of Taiwan; 3School of Medicine, College of Medicine, Chang Gung University, IRF1 and signaling involved in regulating KPNA2 transcription. Western blotting was used Taoyuan, Taiwan; 4Division of Pulmonary to determine the effects of extracellular stimulation and intracellular signaling on the Oncology and Interventional Bronchoscopy, Department of Thoracic modulation of KPNA2-related TF expression. Medicine, Chang Gung Memorial Results: IRF1 was identified as a novel TF that suppresses KPNA2 gene expression. We 5 Hospital, Taoyuan, Taiwan; Department observed that IRF1 expression was lower in cancerous tissues than in normal lung tissues and of Cell and Molecular Biology, College of Medicine, Chang Gung University, that its low expression was correlated with poor prognosis in NSCLC. Notably, both ataxia Taoyuan, Taiwan; 6Molecular Medicine telangiectasia mutated (ATM) and mechanistic target of rapamycin (mTOR) inhibitors Research Center, Chang Gung University, reduced KPNA2 expression, which was accompanied by increased expression of IRF1 but Taoyuan, Taiwan decreased expression of E2F1, a TF that promotes KPNA2 expression in lung ADC cells. *These authors contributed equally to IRF1 knockdown restored the reduced levels of KPNA2 in ATM inhibitor-treated cells. We this work further demonstrated that epidermal growth factor (EGF)-activated mTOR and hypoxia- induced ATM suppressed IRF1 expression but promoted E2F1 expression, which in turn upregulated KPNA2 expression in lung ADC cells. Conclusion: IRF1 acts as a potential tumor suppressor in NSCLC. EGF and hypoxia promote KPNA2 expression by simultaneously suppressing IRF1 expression and enhancing Correspondence: Chia-Jung Yu Department of Cell and Molecular E2F1 expression in lung ADC cells. Our study provides new insights into targeted therapy Biology, College of Medicine, Chang Gung for lung cancer. University, 259 Wen-Hwa 1st Road, Guishan District, Taoyuan City, Taiwan Keywords: lung adenocarcinoma, KPNA2, IRF1, E2F1, EGF, hypoxia Tel +886-3-2118800 ext. 3424 Fax +886-3-2118042 Email [email protected] Introduction Chih-Liang Wang α Division of Pulmonary Oncology and Karyopherin alpha 2 (KPNA2, also known as importin 1) is a member of the Interventional Bronchoscopy, importin α family and transports cargo containing a canonical nuclear localiza- Department of Thoracic Medicine, Chang 1,2 Gung Memorial Hospital, Linkou, 5 Fuxing tion signal by forming an importin α/β/cargo heterotrimer. Due to its function Street, Guishan District, Taoyuan City, in nucleocytoplasmic transport, KPNA2 is involved in many cellular processes, Taiwan Email [email protected] including differentiation, development, viral infection, the immune response, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 11475–11486 11475 DovePress © 2019 Huang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. – http://doi.org/10.2147/OTT.S221832 php and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Huang et al Dovepress transcriptional regulation and cellular maintenance.3 physiological conditions involved in IRF1-mediated Recently, several studies have linked KPNA2 to cancer. KPNA2 expression in lung ADC cells. During the past decade, KPNA2 overexpression has been reported in at least 18 human cancer types, such as lung, Materials and Methods breast, colon and bladder cancer. A high level of KPNA2 Reagents and Antibodies is positively associated with cancer invasiveness and Epidermal growth factor (EGF), rapamycin, ATM inhibitor poor prognosis in patients, thus establishing KPNA2 as and β-actin antibody (MAB1501) were purchased from a potentially relevant therapeutic target.3,4 We previously Millipore (Bedford, MA, USA). KPNA2 (sc-55538), identified KPNA2 as a potential biomarker for lung E2F1 (sc-251), IRF1 (sc-497) and ATM (sc-23921) anti- ADC, and we observed that KPNA2 overexpression pro- bodies were obtained from Santa Cruz (California, USA). motes the proliferation and migration of lung ADC Phospho-ATM (Ser1981), p70S6K, phospho-p70S6K cells.5 We applied proteomic approaches to search for (Thr389), mTOR, phospho-mTOR (Ser2448), IRF1 and differentially expressed protein profiles and invasive- Slug antibodies were obtained from Cell Signaling ness-associated KPNA2−vimentin−pErk complexes in (Beverly, MA, USA). Hypoxia inducible factor 1α (HIF- lung ADC cells with siRNA-mediated knockdown of 1α) and lactate dehydrogenase A (LDHA) antibodies were KPNA2.6,7 Notably, KPNA2 transports the oncogenes purchased from GeneTex (Irvine, California, USA) and c-Myc and E2F1 and the tumor suppressor genes p53, Abcam (Cambridge, Massachusetts, USA), respectively. NBS1 and BRCA1 into the nucleus, suggesting that spatiotemporal regulation of KPNA2 is crucial for its role in tumorigenesis.6,8–10 Our recent study showed Cell Culture that the mTOR pathway is involved in the regulation of A549 ADC, NCI-H520 squamous cell carcinoma (SCC) KPNA2 protein turnover and correlates with Dp1/E2F1- and NCI-H460 large-cell carcinoma (LCC) cell lines were mediated KPNA2 transcription.11 However, the upstream purchased from Food Industry Research and Development signaling pathway and the transcription factor (TF) Institute (Hsinchu, Taiwan). CL1-5 ADC cell line was responsible for regulating KPNA2 expression are still derived from one man with poorly differentiated lung 23 unclear. ADC and kindly provided by Professor P.C. Yang Interferon regulatory factor-1 (IRF1), a TF belonging (Department of Internal Medicine, National Taiwan to the IRF family, regulates IFN-β and IFN-related gene University Hospital, Taipei, Taiwan). A549 cells were ’ fi expression.12 Accumulating evidence supports the notion cultured in Dulbecco s Modi ed Eagle Medium (DMEM, that IRF1 has multiple functions in gene expression reg- Gibco, Invitrogen, Carlsbad, CA, USA), and CL1-5, NCI- ulation during inflammation, immune responses, cell pro- H520 and NCI-H460 cells were cultured in RPMI 1640 liferation, cell cycle progression, T cell differentiation, (Gibco). All media were supplemented with 10% fetal and DNA damage.13–15 Notably, IRF1 is also involved bovine serum (Gibco), 100 units/mL penicillin- in cancer biology, but its role in cancer progression is streptomycin (Gibco), and 2 mM L-glutamine (Gibco). fi controversial. Gene alteration and/or low expression of The cells were incubated at 37°C in a humidi ed atmo- IRF1 are correlated with poorer clinical outcomes, high sphere comprising 95% air/5% CO2. cancer susceptibility and low immunotherapy response, suggesting that IRF1 is a tumor suppressor in multiple Small Interfering RNA Transfection cancer types, such as leukemia, breast cancer, cervical Cells were transfected for 24 h with 10 nM negative control – cancer and colorectal cancer.16 19 However, the onco- (NC) small interfering RNA (siRNA), siRNA against IRF1 genic ability of IRF1 in hepatocellular carcinoma and (GGGCUCAUCUGGAUUAAUA, GCUCAGCUGUGCG esophageal cancer was recently reported.20–22 These stu- AGUGUA, Dharmacon, Lafayette, USA) or siRNA against dies suggest that the role of IRF1 in cancer is cancer-type KPNA2 (GAAAUGAGGCGUCGCAGAA, GAAGCUA specific. CGUGGACAAUGU, AAUCUUACCUGGACACUUU, GU In the present study, we identified IRF1 as a novel AAAUUGGUCUGUUGAUG, Dharmacon, Lafayette, USA) transcriptional suppressor of KPNA2 in lung ADC cells. with Lipofectamine RNAiMAX Transfection Reagent We further investigated the signaling pathways and (Invitrogen, Carlsbad, CA, USA). 11476 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Huang et al Quantitative Reverse Transcription Western Blotting Assay Polymerase
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