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      CircNFIX Acts as a miR-212-3p Sponge to Enhance the Malignant Progression of Non-Small Cell Lung Cancer by Up-Regulating ADAM10

      research-article
      1 , 2 , 3 , 1
      Cancer Management and Research
      Dove
      NSCLC, circNFIX, miR-212-3p, ADAM10, malignant progression

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          Abstract

          Background

          Non-small cell lung cancer (NSCLC) remains the most commonly diagnosed malignancy and the leading cause of cancer death worldwide. Circular RNAs (circRNAs) have been demonstrated to play critical roles in human carcinogenesis, including NSCLC. However, it is still unclear whether circRNA nuclear factor I X (circNFIX) is implicated in the molecular pathogenesis of NSCLC.

          Methods

          The expression levels of circNFIX, miR-212-3p and a disintegrin and metalloproteinases 10 (ADAM10) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell viability was gauged by the Cell Counting Kit-8 (CCK-8) assay, and cell migration and invasion were determined by transwell assays. Glucose uptake and lactate product were determined using the assay kits. Targeted relationships among circNFIX, miR-212-3p and ADAM10 were verified by dual-luciferase reporter and RNA pulldown assays. Additionally, the xenograft model assays were carried out to analyze the role of circNFIX in tumor growth in vivo.

          Results

          Our data revealed that circNFIX was overexpressed in NSCLC and predicted poor prognosis of NSCLC patients. CircNFIX knockdown suppressed NSCLC cell viability, migration, invasion and glycolysis in vitro and hampered tumor growth in vivo. Mechanistically, CircNFIX acted as a molecular sponge of miR-212-3p, and the repressive effect of circNFIX knockdown on NSCLC cell malignant progression was mediated by miR-212-3p. Moreover, ADAM10 was a direct target of miR-212-3p, and circNFIX influenced ADAM10 expression by sponging miR-212-3p in NSCLC cells. Furthermore, the silencing of ADAM10 hindered NSCLC cell viability, migration, invasion and glycolysis in vitro.

          Conclusion

          Our findings first identified that the knockdown of circNFIX, a highly expressed circRNA in NSCLC, exerted a repressive role in NSCLC malignant progression at least in part through targeting the miR-212-3p/ ADAM10 axis, illuminating a novel understanding of circRNA regulation in NSCLC.

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          Most cited references29

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          The circ RNA –micro RNA code: emerging implications for cancer diagnosis and treatment

          Circular RNAs (circRNAs) comprise an emerging new class of endogenous RNAs expressed abundantly by the eukaryotic transcriptome. They are characterized by a covalently closed loop structure, resulting in RNA molecules that are more stable than linear RNAs. A growing number of studies indicate that circRNAs play critical roles in human diseases and show great potential as biomarkers and therapeutic targets. The molecular events determined by circRNA activity, the circRNA code, involve other types of noncoding RNA molecules, primarily microRNAs, long noncoding RNAs, and RNA‐binding proteins. Herein, we mainly focus on the circRNA–microRNA code, showing how this relationship impacts the regulation of gene expression in cancer. The emerging roles for circRNAs in oncogenic pathways highlight new perspectives for the detailed molecular dissection of cancer pathogenesis and, at the same time, offer new opportunities to design innovative therapeutic strategies. Here, we review recent research advancements in understanding the biogenesis, molecular functions, and significance of circRNAs in cancer diagnosis and treatment.
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            Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer

            Circular RNAs are widely expressed in eukaryotic cells and associated with cancer. However, limited studies to date have focused on the potential role of circRNAs in progression of lung cancer. Data from the current investigation showed that circRNA 100146 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and the chemically induced malignant transformed bronchial cell line, 16HBE-T, as well as 40 paired tissue samples of NSCLC. Suppression of circRNA 100146 inhibited the proliferation and invasion of cells and promoted apoptosis. Furthermore, circRNA 100146 could interact with splicing factors and bind miR-361-3p and miR-615-5p to regulate multiple downstream mRNAs. Our collective findings support a role of circRNA 100146 in the development of NSCLC and further demonstrate endogenous competition among circRNA 100146, SF3B3 and miRNAs, providing novel insights into the mechanisms underlying non-small cell lung cancer. Electronic supplementary material The online version of this article (10.1186/s12943-019-0943-0) contains supplementary material, which is available to authorized users.
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              Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2).

              Impaired macroautophagy/autophagy and high levels of glycolysis are prevalent in liver cancer. However, it remains unknown whether there is a regulatory relationship between autophagy and glycolytic metabolism. In this study, by utilizing cancer cells with basal or impaired autophagic flux, we demonstrated that glycolytic activity is negatively correlated with autophagy level. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. In a tissue microarray of human liver cancer, the combination of high HK2 expression and high SQSTM1 expression was shown to have biological and prognostic significance. Furthermore, 3-BrPA, a pyruvate analog targeting HK2, significantly decreased the growth of autophagy-impaired tumors in vitro and in vivo (p < 0.05). By demonstrating the regulation of glycolysis by autophagy through the TRAF6- and SQSTM1-mediated ubiquitination system, our study may open an avenue for developing a glycolysis-targeting therapeutic intervention for treatment of autophagy-impaired liver cancer.
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                Author and article information

                Journal
                Cancer Manag Res
                Cancer Manag Res
                cmar
                cancmanres
                Cancer Management and Research
                Dove
                1179-1322
                02 October 2020
                2020
                : 12
                : 9577-9587
                Affiliations
                [1 ]SSL Central Hospital of Dongguan City (The Third People’s Hospital of Dongguan City) , Dongguan, People’s Republic of China
                [2 ]Information Section, SSL Central Hospital of Dongguan City (The Third People’s Hospital of Dongguan City) , Dongguan, People’s Republic of China
                [3 ]Department of Clinical Pharmacy, SSL Central Hospital of Dongguan City (The Third People’s Hospital of Dongguan City) , Dongguan, People’s Republic of China
                Author notes
                Correspondence: Jun LuSSL Central Hospital of Dongguan City (The third people’s hospital of Dongguan City) , No. 01, Huangzhou Xianglong Road, Shilong Town, Dongguan, Guangdong523326, People’s Republic of ChinaTel +86 0769-81368187 Email t4377u@163.com
                Article
                272309
                10.2147/CMAR.S272309
                7537990
                33061643
                6702cad6-980c-4429-8ade-ba42b3748e5e
                © 2020 Lu 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 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).

                History
                : 15 July 2020
                : 31 August 2020
                Page count
                Figures: 6, Tables: 3, References: 41, Pages: 11
                Funding
                Funded by: the Medical Scientific Research Foundation of Guangdong Province, China;
                Funded by: Scientific Research Project of Traditional Chinese Medicine Bureau of Guangdong Province, China;
                This work was supported by the Medical Scientific Research Foundation of Guangdong Province, China (No.B2017033) and Scientific Research Project of Traditional Chinese Medicine Bureau of Guangdong Province, China (No.20171273; No.20201368).
                Categories
                Original Research

                Oncology & Radiotherapy
                nsclc,circnfix,mir-212-3p,adam10,malignant progression
                Oncology & Radiotherapy
                nsclc, circnfix, mir-212-3p, adam10, malignant progression

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