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Circ_0000442 functions as a tumor repressor in breast cancer by impacting miR-1229-3p and upregulating ZBTB1


A variety of circular RNAs (circRNAs) have tumor-regulatory roles in breast cancer (BC). Circ_0000442 was reported to inhibit the progression of BC, and this study was designed to explore the novel functional mechanism of circ_0000442 in BC. The expression analysis for circ_0000442, microRNA-1229-3p (miR-1229-3p) and zinc finger and BTB domain containing 1 (ZBTB1) was performed using the quantitative real-time polymerase chain reaction (qRT-PCR). Dual-luciferase reporter assay was used to affirm the target interaction. Cell proliferation was examined using Edu assay and colony formation assay. Cell migration and invasion were assessed by transwell assay. Flow cytometry was applied for the detection of cell apoptosis. Glycolysis was analyzed using the detection kits to measure the glucose consumption and lactate production. The protein expression levels were determined by western blot. The role of circ_0000442 in BC in vivo was explored using tumor xenograft assay. Circ_0000442 expression was downregulated and miR-1229-3p expression was upregulated in BC tissues and cells. Circ_0000442 directly interacted with miR-1229-3p. Circ_0000442 repressed proliferation, migration, invasion and glycolysis but promoted apoptosis in BC cells. The anti-tumor role of circ_0000442 was attributed to the sponge effect on miR-1229-3p. ZBTB1 was a downstream target for miR-1229-3p. Downregulation of miR-1229-3p blocked the malignant behaviors in BC cells by elevating the expression of ZBTB1. Circ_0000442 regulated the ZBTB1 level by targeting miR-1229-3p, and it inhibited tumor growth of BC in vivo by mediating the miR-1229-3p/ZBTB1 axis. All evidence unraveled that circ_0000442 impeded the progression of BC by sponging miR-1229-3p to evoke the ZBTB1 expression upregulation.

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Data availability

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.


  • Chen RX, Liu HL, Yang LL, Kang FH, Xin LP, Huang LR, Guo QF, Wang YL (2019) Circular RNA circRNA_0000285 promotes cervical cancer development by regulating FUS. Eur Rev Med Pharmacol Sci 23(20):8771–8778

    PubMed  Google Scholar 

  • Chen C, Huang Z, Mo X, Song Y, Li X, Li X, Zhang M (2020) The circular RNA 001971/miR-29c-3p axis modulates colorectal cancer growth, metastasis, and angiogenesis through VEGFA. J Exp Clin Cancer Res 39(1):91

    CAS  Article  Google Scholar 

  • Coleman RE, Croucher PI, Padhani AR, Clezardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L (2020) Bone metastases. Nat Rev Dis Primers 6(1):83

    Article  Google Scholar 

  • Das PK, Rakib MA, Khanam JA, Pillai S, Islam F (2019) Novel therapeutics against breast cancer stem cells by targeting surface markers and signaling pathways. Curr Stem Cell Res Ther 14(8):669–682

    CAS  Article  Google Scholar 

  • Feng S, Liu N, Chen X, Liu Y, An J (2020) Long non-coding RNA NEAT1/miR-338-3p axis impedes the progression of acute myeloid leukemia via regulating CREBRF. Cancer Cell Int 20:112

    CAS  Article  Google Scholar 

  • Ganapathy-Kanniappan S (2018) Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol 53(6):667–682

    CAS  Article  Google Scholar 

  • Gao S, Yu Y, Liu L, Meng J, Li G (2019) Circular RNA hsa_circ_0007059 restrains proliferation and epithelial-mesenchymal transition in lung cancer cells via inhibiting microRNA-378. Life Sci 233:116692

    CAS  Article  Google Scholar 

  • Hu Y, Guo F, Zhu H, Tan X, Zhu X, Liu X, Zhang W, Yang Q, Jiang Y (2020) Circular RNA-0001283 suppresses breast cancer proliferation and invasion via MiR-187/HIPK3 axis. Med Sci Monit 26:e921502

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang W, Lu Y, Wang F, Huang X, Yu Z (2020) Circular RNA circRNA_103809 accelerates bladder cancer progression and enhances chemo-resistance by activation of miR-516a-5p/FBXL18 axis. Cancer Manage Res 12:7561–7568

    CAS  Article  Google Scholar 

  • Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20(11):675–691

    CAS  Article  Google Scholar 

  • Lei B, Tian Z, Fan W, Ni B (2019) Circular RNA: a novel biomarker and therapeutic target for human cancers. Int J Med Sci 16(2):292–301

    CAS  Article  Google Scholar 

  • Li Z, Chen Z, Hu G, Jiang Y (2019) Roles of circular RNA in breast cancer: present and future. Am J Transl Res 11(7):3945–3954

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liang Y, Zhang H, Song X, Yang Q (2020) Metastatic heterogeneity of breast cancer: molecular mechanism and potential therapeutic targets. Semin Cancer Biol 60:14–27

    CAS  Article  Google Scholar 

  • Liu Y, Yang C, Zhao Y, Chi Q, Wang Z, Sun B (2019) Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis. Aging (albany NY) 11(24):12328–12344

    CAS  Article  Google Scholar 

  • Liu T, Ye P, Ye Y, Lu S, Han B (2020) Circular RNA hsa_circRNA_002178 silencing retards breast cancer progression via microRNA-328-3p-mediated inhibition of COL1A1. J Cell Mol Med 24(3):2189–2201

    CAS  Article  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408

    CAS  Article  Google Scholar 

  • Lyons TG (2019) Targeted therapies for triple-negative breast cancer. Curr Treat Options Oncol 20(11):82

    Article  Google Scholar 

  • Misir S, Hepokur C, Aliyazicioglu Y, Enguita FJ (2020) Circular RNAs serve as miRNA sponges in breast cancer. Breast Cancer 27(6):1048–1057

    Article  Google Scholar 

  • Morgan AJ, Giannoudis A, Palmieri C (2021) The genomic landscape of breast cancer brain metastases: a systematic review. Lancet Oncol 22(1):e7–e17

    CAS  Article  Google Scholar 

  • Nagini S (2017) Breast cancer: current molecular therapeutic targets and new players. Anticancer Agents Med Chem 17(2):152–163

    CAS  Article  Google Scholar 

  • Nishibeppu K, Komatsu S, Imamura T, Kiuchi J, Kishimoto T, Arita T, Kosuga T, Konishi H, Kubota T, Shiozaki A et al (2020) Plasma microRNA profiles: identification of miR-1229-3p as a novel chemoresistant and prognostic biomarker in gastric cancer. Sci Rep 10(1):3161

    CAS  Article  Google Scholar 

  • Pan G, Mao A, Liu J, Lu J, Ding J, Liu W (2020) Circular RNA hsa_circ_0061825 (circ-TFF1) contributes to breast cancer progression through targeting miR-326/TFF1 signalling. Cell Prolif 53(2):e12720

    Article  Google Scholar 

  • Qi C, Qin X, Zhou Z, Wang Y, Yang Q, Liao T (2020) Circ_0072995 promotes cell carcinogenesis via up-regulating miR-149-5p-mediated SHMT2 in breast cancer. Cancer Manage Res 12:11169–11181

    CAS  Article  Google Scholar 

  • Shi Y, Fang N, Li Y, Guo Z, Jiang W, He Y, Ma Z, Chen Y (2020) Circular RNA LPAR3 sponges microRNA-198 to facilitate esophageal cancer migration, invasion, and metastasis. Cancer Sci 111(8):2824–2836

    CAS  Article  Google Scholar 

  • Tan Z, Zheng H, Liu X, Zhang W, Zhu J, Wu G, Cao L, Song J, Wu S, Song L et al (2016) MicroRNA-1229 overexpression promotes cell proliferation and tumorigenicity and activates Wnt/beta-catenin signaling in breast cancer. Oncotarget 7(17):24076–24087

    Article  Google Scholar 

  • Teng F, Xu J, Zhang M, Liu S, Gu Y, Zhang M, Wang X, Ni J, Qian B, Shen R et al (2019) Comprehensive circular RNA expression profiles and the tumor-suppressive function of circHIPK3 in ovarian cancer. Int J Biochem Cell Biol 112:8–17

    CAS  Article  Google Scholar 

  • Wu F, Wang F, Yang Q, Zhang Y, Cai K, Liu L, Li S, Zheng Y, Zhang J, Gui Y et al (2020) Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes. In Vitro Cell Dev Biol Anim 56(10):866–877

    CAS  Article  Google Scholar 

  • Xia M, Feng S, Chen Z, Wen G, Zu X, Zhong J (2020) Non-coding RNAs: key regulators of aerobic glycolysis in breast cancer. Life Sci 250:117579

    CAS  Article  Google Scholar 

  • Yue F, Peng K, Zhang L, Zhang J (2021) Circ_0004104 accelerates the progression of gastric cancer by regulating the miR-539–3p/RNF2 axis. Dig Dis Sci.

    Article  PubMed  Google Scholar 

  • Zhang XY, Mao L (2021) Circular RNA Circ_0000442 acts as a sponge of MiR-148b-3p to suppress breast cancer via PTEN/PI3K/Akt signaling pathway. Gene 766:145113

    CAS  Article  Google Scholar 

  • Zhang W, Mao S, Shi D, Zhang J, Zhang Z, Guo Y, Wu Y, Wang R, Wang L, Huang Y et al (2019) MicroRNA-153 decreases tryptophan catabolism and inhibits angiogenesis in bladder cancer by targeting indoleamine 2,3-dioxygenase 1. Front Oncol 9:619

    Article  Google Scholar 

  • Zhang P, Yang Y, Qian K, Li L, Zhang C, Fu X, Zhang X, Chen H, Liu Q, Cao S et al (2020) A novel tumor suppressor ZBTB1 regulates tamoxifen resistance and aerobic glycolysis through suppressing HER2 expression in breast cancer. J Biol Chem 295(41):14140–14152

    CAS  Article  Google Scholar 

  • Zhang CC, Li Y, Feng XZ, Li DB (2021) Circular RNA circ_0001287 inhibits the proliferation, metastasis, and radiosensitivity of non-small cell lung cancer cells by sponging microRNA miR-21 and up-regulating phosphatase and tensin homolog expression. Bioengineered 12(1):414–425

    CAS  Article  Google Scholar 

  • Zhao X, Cui L (2020) A robust six-miRNA prognostic signature for head and neck squamous cell carcinoma. J Cell Physiol 235(11):8799–8811

    CAS  Article  Google Scholar 

  • Zhou SY, Chen W, Yang SJ, Xu ZH, Hu JH, Zhang HD, Zhong SL, Tang JH (2019) The emerging role of circular RNAs in breast cancer. Biosci Rep.

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Correspondence to Jianhui Liu.

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The present study was approved by the ethical review committee of The Second Affiliated Hospital of Nanchang University. Written informed consent was obtained from all enrolled patients.

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Liu, J., Liu, J. Circ_0000442 functions as a tumor repressor in breast cancer by impacting miR-1229-3p and upregulating ZBTB1. Mamm Genome 33, 543–554 (2022).

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