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EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating Mmps

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EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating Mmps OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs This article was published in the following Dove Press journal: OncoTargets and Therapy Liang Song1,* Background: Epidermal growth factor-containing fibulin-like extracellular matrix protein 2 Xiang-Xin Li2,* (EFEMP2), also known as fibulin-4, MBP1 and UPH1, is an extracellular matrix protein Xiang-Yan Liu1 associated with a variety of tumors. The purpose of this study was to investigate the Zhou Wang1 prognostic value and the function of EFEMP2 in lung cancer. Yang Yu 1 Methods: The mRNA and protein expression of EFEMP2 in lung normal and cancer tissues, lung cancer cell lines (A549, H460, H1299 and H1650) and normal epithelial cell Mo Shi1 line BEAS-2B were evaluated by immunohistochemistry, RT-qPCR and Western blotting. Bin Jiang1 1 The Public databases (Oncomine and Kaplan-Meier plotter) were used to investigate the Xiao-Peng He prognostic value of EFEMP2 in lung cancer. RNA interference (RNAi) and overexpression 1Department of Thoracic Surgery, transfection were performed to detect the effects of EFEMP2 up- or down-regulation on lung fi Shandong Provincial Hospital Af liated to normal and cancer cell proliferation, invasion and metastasis in vitro and in vivo. Shandong University, Jinan, Shandong, People’s Republic of China; 2Department Results: EFEMP2 was lowly expressed in lung cancer tissues and cells, and its low of Hematology, Qilu Hospital of expression was associated with malignant phenotype and poor prognosis of lung cancer. Shandong University, Jinan, Shandong, The same conclusion had been drawn from the Public databases. EFEMP2 overexpression People’s Republic of China significantly inhibited the invasion of lung cancer cells, hampered the process of EMT, and *These authors contributed equally to decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown this work remarkably enhanced the invasion of lung cancer cells, promoted EMT, and increased the expression and activity of MMP2 and MMP9. Conclusion: The low expression of EFEMP2 was detected in lung cancer and was posi- tively correlated with the poor prognosis of patients. EFEMP2 was a tumor suppressor gene that inhibited the progress of lung cancer, which suggested a new research objective for the future studies. Keywords: EFEMP2, lung cancer, invasion, metastasis, EMT, MMPs Introduction Lung cancer occurs in the bronchial mucosal epithelium, and the incidence of lung cancer has been significantly increased in the last 50 years. In the industrial developed countries of Europe and America and some big industrial cities in China, the incidence of lung cancer has ranked first among male malignant tumors, and the incidence of Correspondence: Xiao-Peng He Department of Thoracic Surgery, lung cancer in women has also increased rapidly, accounting for the second or third Shandong Provincial Hospital Affiliated to place of women common malignant tumors. There are about 1.8 million new cases of Shandong University, 324 Jing Wu Road, Jinan, Shandong Province 250021, People’s lung cancer worldwide each year, with more than 1.6 million deaths. Lung cancer has Republic of China become a major disease endangering life and health.1 The early diagnosis of lung Tel/Fax +86-531-6877-7884 Email [email protected] cancer is difficult. About 85% of the patients are in the advanced stage of diagnosis, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2020:13 1375–1396 1375 DovePress © 2020 Song 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.php – http://doi.org/10.2147/OTT.S236111 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). Song et al Dovepress and the effect of surgical treatment is not ideal. The 5-year in human endometrial carcinoma, EFEMP2 demonstrated survival rate is only 16%, which is in sharp contrast to the inhibitory effects in tumor invasion and metastasis.20 These high survival rate of 90%, 65% and nearly 100% for breast ostensibly contradictory findings in different cancers may cancer, colon cancer and prostate cancer, respectively.2 reflect “context-specific” roles of EFEMP2. Little is known Surgical treatment has been recognized as the first choice about the direct molecular function of EFEMP2 in cancer for the treatment of lung cancer, but most of the patients progressions. Till now, the function of EFEMP2 in lung cancer missed the opportunity of radical surgery, and the invasion, has not been explored, so the purpose of this study is to detect metastasis and poor prognosis of advanced tumors are still the expression of EFEMP2 in lung cancer and its relationship difficult to solve. Gene therapy and targeted therapy have with the progress of lung cancer. been paid more and more attention as a new generation model of tumor therapy. Molecular targeted drugs can spe- Materials and Methods cifically select carcinogenic sites and kill tumor cells without Tumor Tissues Samples affecting the normal tissue cells around them. Therefore, With the written informed consent of the patients, a total of molecular targeted therapy is also known as “biological 415 lung tissue samples (68 normal lung tissue and 347 non- missiles”. Compared with traditional chemotherapeutic small cell lung cancer) were collected from Shandong drugs, molecular targeted drugs have the advantages of Provincial Hospital between 2005 and 2017. Non-small cell strong specificity, obvious curative effect and less side lung cancer (NSCLC) patients were diagnosed according to effects. However, no specific markers have been found in the 8th edition of the tumor-node-metastasis (TNM) classifi- the treatment of lung cancer, and there is a lack of under- cation of lung cancer recommended by the International standing of the molecular mechanism of invasion and Association for the Study of Lung Cancer (IASLC) staging metastasis.3 therefore, clarifying the mechanism of lung committee. None of them had received radiotherapy or che- cancer invasion and metastasis and finding effective target- motherapy before surgery. This study was approved by the ing drugs to inhibit invasion and metastasis is essential to Institutional Medical Ethics Committee of Shandong fully improve the prognosis of patients. Provincial Hospital Affiliated to Shandong University and Epidermal growth factor-containing fibulin-like extracel- all methods were carried out in accordance with the relevant lular matrix protein 2 (EFEMP2, also known as fibulin-4, guidelines and regulations. MBP1 and UPH1), is a member of fibulin glycoprotein family.4–6 Fibulins are a family of seven extracellular matrix proteins characterized by a tandem array of calcium-binding Cell Lines A549, H460, H1299, H1650 (human lung cancer cell lines), (cb) epidermal growth factor (EGF)-like modules and – and BEAS-2B (normal lung epithelial cell line) were obtained a fibulin-type C-terminal domain.7 9 EFEMP2 is a 443 from the Cell Resource Center of Shanghai Institutes for amino acid secretory protein and contains of a N-terminal Biological Sciences, Chinese Academy of Sciences. All cells modified cbEGF module, five consecutive cbEGF modules were cultured in Gibco™ Dulbecco’sModified Eagle and the FC domain.4 EFEMP2 is often found in tissues and Medium: Nutrient Mixture F-12 (DMEM/F-12, SIGMA, organs that are rich in elastic fibers, including the blood RNBG3415, UK) media supplemented with 10% Gibco™ vessels, heart valves, lung and skin.7,10 This gene is necessary fetal bovine serum (FBS, Australia origin) and 1% Gibco® for elastic fiber formation and connective tissue development, Antibiotic ((100 µg/mL streptomycin, 100 U/mL penicillin, and plays an important role in stabilizing the extracellular Millipore, 61207–1, USA), at 37 °C in a 5% CO incubator. matrix structure.11,12 DefectsofEFEMP2inpatientshave 2 Cells were routinely tested every 3 months for Mycoplasma been linked to many diseases, such as autosomal recessive with QuickTest Mycoplasma Detection Kit (Biotool, Houston, cutis laxa syndrome, aneurysms and tortuosity of the large TX, USA), and cultured for no longer than 15 passages. arteries, developmental emphysema, diaphragmatic and ingu- inal hernia, joint laxity and cancer.13–15 The role of EFEMP2 in tumorigenesis has not yet been fully elucidated, both carci- Immunohistochemistry (IHC) and nogenic and anti-carcinogenic effects have been reported. Immunocytochemistry (ICC) High expression of EFEMP2 was associated with tumor pro- For IHC of the samples, tissue blocks were fixedbyformalin, gress and poor prognosis in cervical carcinoma,16 ovarian embedded in paraffin and then cut into 5-μm thick sections. carcinoma,17 glioblastoma18 and osteosarcoma.19 However, After xylene dewaxing, gradient ethanol rehydration and 1376 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2020:13 DovePress Dovepress Song et al high-pressure antigen retrieval, tissue sections were stained between clinical lung cancer specimens and normal con- with the selected streptavidin–biotin–peroxidase (SP) staining trols. The detailed information of standardization technol- method. For ICC of the samples, cells in logarithmic growth ogy and statistical calculation is provided on Oncomine were harvested and seeded into cell culture dishes covered with platform. The prognostic value of EFEMP2 in patients coverslips. After 24 h of adhesion, the cell coverslips were with lung cancer was investigated in Kaplan-Meier fixed with 95% ethanol for 30 min and then stained by the same Plotter public databases (http://kmplot.com/analysis/). SP staining method as IHC.
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