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Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 Via Down-Regulating Mir-33A-5P

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Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 Via Down-Regulating Mir-33A-5P OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p This article was published in the following Dove Press journal: OncoTargets and Therapy Shimin Wu 1 Background: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepato- Hongwu Ai2 cellular carcinoma (HCC). EGOT is a long non-coding RNA (lncRNA) induced after HCV Kehui Zhang3,4 infection that increases viral replication by antagonizing the antiviral response. Interestingly, Hao Yun3,4 EGOTalso acts as a crucial regulator in multiple cancers. However, its role in HCC remains unclear. Fei Xie3,4 Methods: Real-time PCR (RT-PCR) was used to detect the expression of EGOT in HCC samples and cell lines. CCK-8 assay and colony formation assay were performed to evaluate 1 Center for Clinical Laboratory, General the effect of EGOT on proliferation. Scratch healing assay and transwell assay were used to Hospital of the Yangtze River Shipping, Wuhan Brain Hospital, Wuhan 430030, detect the changes of migration and invasion. Flow cytometry was used to detect the effect of People’s Republic of China; 2Center for EGOT on apoptosis. Interaction between EGOT and miR-33a-5p was determined by bioin- Clinical Laboratory, Wuhan Kangjian formatics analysis, RT-PCR, and dual-luciferase reporter assay. Western blot was used to Maternal and Infant Hospital, Wuhan 430050, People’s Republic of China; confirm that high mobility group protein A2 (HMGA2) could be modulated by EGOT. 3Wuhan Center for Clinical Laboratory, Results: Compared with normal liver tissues, the expression level of EGOT in HCC tissues Wuhan Fourth Hospital, Wuhan 430030, fi People’s Republic of China; 4Puai Hospital, was signi cantly up-regulated. EGOT markedly regulated viability, migration and invasion Tongji Medical College, Huazhong of HCC cells. The expression level of EGOT was negatively correlated the expression level University of Science and Technology, of miR-33a-5p. It is also confirmed that EGOT could specifically bind to miR-33a-5p and Wuhan 430032, People’s Republic of China could reduce its expression, in turn, up-regulate the expression of HMGA2. Conclusion: Our data imply that EGOT may be a novel therapeutic target for HCC, and highlights the key role of EGOT/miR-33a-5p/HMGA2 in the progression of this deadly disease. Keywords: HCV, HCC, EGOT, miR-33a-5p, HMGA2 Introduction Hepatic carcinoma (HCC), one of the common tumors of the digestive system, is featured by insidious onset, rapid development and high mortality. It is reported that HCC is the fifth largest type of cancer in the world and the third common cause of death related to cancer.1 In China, nearly 400,000 people die of HCC each year.2 The pathogenic factors include environmental factors, genetic variation, eating habits, etc., among which the most important ones are hepatitis B virus (HBV) and/or hepatitis 3 Correspondence: Shimin Wu C virus (HCV) infection. At present, the treatment strategies of HCC include surgery, General Hospital of the Yangtze River ’ chemotherapy, target therapy, etc., but the prognosis of patients with HCC is still Shipping, Building 5, Huiji Road, Jiang an 4,5 District, Wuhan 430030, People’s unsatisfactory due to postoperative recurrence and metastasis. Therefore, it is of Republic of China significance to study the potential biological mechanisms in the progression of HCC for Tel +86 2783782519 Email [email protected] the prevention and treatment of this disease. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 11623–11635 11623 DovePress © 2019 Wu 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.S218308 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). Wu et al Dovepress Long non-coding RNAs (lncRNAs) are a class of RNA and tumorigenesis.23 HMGA2 is overexpressed in many molecules that are more than 200 nucleotides in length epithelial malignancies, such as breast cancer, lung cancer, without protein-coding ability. Although many lncRNAs pancreas cancer and oral squamous cell carcinoma.24–27 are unable to translate proteins, they play an important role Studies have shown that HMGA2 can affect tumor angio- in various biological processes.6,7 A large number of stu- genesis and interfere with the cell cycle, promote tumor dies have shown that lncRNAs can affect the progression cells to obtain stem cell characteristics and undergo EMT, of many types of tumor.8–10 For example, lncRNA OR3A4 thereby maintaining the ability of tumor cells to proliferate, promotes the growth, invasion and metastasis of gastric differentiate, invade, metastasize and self-renew.28,29 The cancer by up-regulating the expression of guanine- targeted regulation of HMGA2 expression by miR-33a-5p nucleotide-binding protein beta polypeptide 2-like 1;11 has been demonstrated in a previous study: miR-33-5p the up-regulated expression of lncRNA ZFAS1 is asso- promotes osteoblast differentiation by directly targeting ciated with the epithelial-mesenchymal transition (EMT) the 3ʹUTR of HMGA2.30 of breast cancer cells;12 and lncRNA HCAL, as ceRNA of Through bioinformatics analysis, we found that there was lysosomal-associated transmembrane protein 4B, promotes a mutual binding site between EGOT and miR-33a-5p, indi- the growth and metastasis of HCC.13 In addition, studies cating that the upregulation of the former in tumor tissues have shown that EGOT promotes the development and may inhibit the expression of the latter. This study was progression of gastric cancer;14 and it is a lncRNA induced designed to detect the expression level of EGOT in HCC by HCV infection, and increases viral replication by coun- tissues and cells, and explore its effects on the expression teracting antiviral responses.15 However, the role of EGOT levels of miR-33a-5p and HMGA2, providing a new theore- in HCC is currently unclear. tical basis for the clinical treatment of HCC. MicroRNAs (MiRs) are a group of highly conserved endogenous non-coding RNA molecules, about 21 to 25nt Materials and Methods in length. They play an important role in cell differentia- tion, metabolism, proliferation, and apoptosis.16 For exam- Pathological Tissue Collection The tissue samples of 52 patients with HCC who under- ple, miR-212 downregulates the methyl CpG binding went HCC removal from the Department of Hepatobiliary protein MeCP2, and promotes the development and pro- Surgery of Wuhan Fourth Hospital from December 2013 gression of gastric cancer;17 and miR-143 is underex- to December 2015 were selected. No patients received pressed in TW01 nasopharyngeal carcinoma cells under adjuvant therapies such as chemotherapy or radiotherapy the action of TGF-β1 cytokines.18 Studies have shown that before surgery. Specimens of the control group were the tumor suppressor miR-33a-5p is a potential biomarker obtained from paracancerous tissues of the same patient for early diagnosis of lung cancer;19 and miR-33a-5p (at least 3cm from the surgical margin), and no cancer inhibits EMT of non-small cell carcinoma, and is cells were found after postoperative pathological examina- a prognostic factor for patients.20 The role of miR-33a- tion. All specimens were placed in liquid nitrogen at 5p in the development and progression of HCC requires −196°C immediately after removal. All patients provided further research. Previous articles have revealed that written informed consent, and that this was conducted in lncRNA directly interacts with miRNAs and regulates accordance with the Declaration of Helsinki. their expression. For example, in osteosarcoma, overex- pression of lncRNA DANCR inhibits the expression of miR-33a-5p;21 and in tongue squamous carcinoma, Cell Culture lncRNA CASC15 targetedly inhibits miR-33a-5p.22 The normal liver cell line L02 and the HCC cell lines However, the interaction between EGOT and miR-33a-5p Hep3B, Huh7, and SMMC-7721 were provided by the has not been elucidated. Clinical Management Center of Wuhan Fourth Hospital. High mobility group protein A2 (HMGA2) gene, All cells were cultured in DMEM medium (Thermo) a small non-histone chromosomal protein, is located in added with 10% fetal bovine serum (Gibco Thermo Fisher 12q13-15. It can bind to chromatin to change its structure Scientific), and 1% penicillin/streptomycin (Invitrogen), and or directly interacts with its related proteins and participates placed in an incubator at 5% CO2 and 37°C. The medium in enhancer formation to regulate the transcription of genes, was changed once every 2 days until the cells were spread which in turn affects embryogenesis, tissue development over the bottom of the flask for passage. The cells were 11624 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2019:12 DovePress Dovepress Wu et al passaged after 0.25% trypsin digestion, and taken in the Table 1 Primers Used in This Study logarithmic growth phase for the experiment. And the use Name Primer Sequences of the cell lines was approved by the Clinical Ethics LncRNA EGOT Forward:5ʹ-CACTGCACAGGGAAACACAAA-3’ Committee of Wuhan Fourth Hospital. Reverse:5ʹ-ACCCTGTTCATAAGCCCTGATG-3’ Cell Transfection miR-33a-5p Forward:5ʹ-GGTGCATTGTAGTTGCATTGC-3’ Reverse:5ʹ-GTGCAGGGTCCGAGGTATTC-3’ The cells were rinsed with PBS buffer (Thermo), for 3 times, trypsinized for 2min, and transferred to a sterile GAPDH Forward:5ʹ-AGCCACATCGCTCAGACAC-3’ ʹ ’ 15mL centrifuge tube.
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