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      • Record: found
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      Is Open Access

      Circ_0000376 regulates miR-577/HK2/LDHA signaling pathway to promote the growth, invasion and glycolysis of osteosarcoma

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          Abstract

          Background

          Many studies have confirmed that circular RNAs (circRNAs) mediate the malignant progression of various tumors including osteosarcoma (OS). Our study is to uncover novel molecular mechanisms by which circ_0000376 regulates OS progression.

          Methods

          The expression of circ_0000376, microRNA (miR)-577, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) was determined by quantitative real-time PCR. OS cell proliferation, apoptosis and invasion were measured using cell counting kit 8 assay, colony formation assay, EdU assay, flow cytometry and transwell assay. Besides, cell glycolysis was assessed by testing glucose consumption, lactate production, and ATP/ADP ratios. Protein expression was examined by western blot analysis. The interaction between miR-577 and circ_0000376 or HK2/LADA was verified by dual-luciferase reporter assay. The role of circ_0000376 on OS tumor growth was explored by constructing mice xenograft models.

          Results

          Circ_0000376 had been found to be upregulated in OS tissues and cells. Functional experiments revealed that circ_0000376 interference hindered OS cell growth, invasion and glycolysis. Circ_0000376 sponged miR-577 to reduce its expression. In rescue experiments, miR-577 inhibitor abolished the regulation of circ_0000376 knockdown on OS cell functions. MiR-577 could target HK2 and LDHA in OS cells. MiR-577 suppressed OS cell growth, invasion and glycolysis, and these effects were reversed by HK2 and LDHA overexpression. Also, HK2 and LDHA expression could be regulated by circ_0000376. In vivo experiments showed that circ_0000376 knockdown inhibited OS tumorigenesis.

          Conclusion

          Circ_0000376 contributed to OS growth, invasion and glycolysis depending on the regulation of miR-577/HK2/LDHA axis, providing a potential target for OS treatment.

          Graphical Abstract

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13018-023-04520-y.

          Highlights

          • Circ_0000376 knockdown inhibits OS development and tumor growth.

          • Circ_0000376 sponges miR-577.

          • MiR-577 targets HK2 and LDHA.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13018-023-04520-y.

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          Most cited references42

          • Record: found
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          The biogenesis, biology and characterization of circular RNAs

          Lasse S. Kristensen, Maria Andersen, Lotte V. W. Stagsted … (2019)
          Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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            Regulation of circRNA biogenesis.

            Ling-Ling Chen, Li. Yang (2015)
            Unlike linear RNAs terminated with 5' caps and 3' tails, circular RNAs are characterized by covalently closed loop structures with neither 5' to 3' polarity nor polyadenylated tail. This intrinsic characteristic has led to the general under-estimation of the existence of circular RNAs in previous polyadenylated transcriptome analyses. With the advent of specific biochemical and computational approaches, a large number of circular RNAs from back-spliced exons (circRNAs) have been identified in various cell lines and across different species. Recent studies have uncovered that back-splicing requires canonical spliceosomal machinery and can be facilitated by both complementary sequences and specific protein factors. In this review, we highlight our current understanding of the regulation of circRNA biogenesis, including both the competition between splicing and back-splicing and the previously under-appreciated alternative circularization.
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              Osteosarcoma.

              J. Ritter, S.S. Bielack (2010)
              The successful treatment of patients with osteosarcoma requires close cooperation within an experienced multidisciplinary team including pediatric or medical oncologists, surgeons, pathologists and radiologists. Therefore, therapy should be performed in specialized centers able to provide access to the full spectrum of care. As in other rare malignancies, treatment should be administered within prospective multicenter trials. Therapy must include complete surgical removal of all detectable tumor sites as well as multiagent chemotherapy. The chemotherapy regimen should include several or all of the following four drugs: doxorubicin, high-dose methotrexate with leukovorin-rescue, cisplatin and ifosfamide. Preoperative (neoadjuvant) plus postoperative (adjuvant) polychemotherapy should be preferred, because it allows preparation for safe surgery and preparation of the appropriate prosthesis for the individual patient. The choice of the postponed definitive surgical procedure should be influenced by the anatomical site of the primary tumor, its relationship to neighboring structures, such as vessels and nerves, age and growth potential of the patient, and probably also by the response of the tumor to preoperative chemotherapy. A major, as yet unsolved, problem is the dismal prognosis for patients with unresectable or relapsed osteosarcomas. Novel approaches are needed in order to improve their prognosis.
              Article 0 comments Cited 397 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Zongwei Li: lzw_mysgkyy@163.com
                Journal
                Journal ID (nlm-ta): J Orthop Surg Res
                Journal ID (iso-abbrev): J Orthop Surg Res
                Title: Journal of Orthopaedic Surgery and Research
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1749-799X
                Publication date (Electronic): 13 January 2024
                Publication date PMC-release: 13 January 2024
                Publication date Collection: 2024
                Volume: 19
                Electronic Location Identifier: 67
                Affiliations
                [1 ]GRID grid.452803.8, Department of Oncology, , The Third Hospital of Mianyang, Sichuan Mental Health Center, ; Mianyang, Sichuan China
                [2 ]Department of Foot and Ankle Surgery, Mianyang Orthopedic Hospital, No.30, Nanhe Road, Fucheng District, Mianyang City, 621000 Sichuan China
                Article
                Publisher ID: 4520
                DOI: 10.1186/s13018-023-04520-y
                PMC ID: 10788008
                PubMed ID: 38218855
                SO-VID: 8e4d891c-6138-438a-bf93-6c973250d305
                Copyright © © The Author(s) 2024
                License:

                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.

                History
                Date received : 19 October 2023
                Date accepted : 29 December 2023
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © BioMed Central Ltd., part of Springer Nature 2024

                ScienceOpen disciplines: Surgery
                Keywords: osteosarcoma,circ_0000376,mir-577,hk2,ldha
                Data availability:
                ScienceOpen disciplines: Surgery
                Keywords: osteosarcoma, circ_0000376, mir-577, hk2, ldha

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