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Circ-VPS18 Knockdown Enhances TMZ Sensitivity and Inhibits Glioma Progression by MiR-370/RUNX1 Axis

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Abstract

Glioma is a prevalent primary brain tumor. Temozolomide (TMZ) has been used to treat glioma. However, the resistance of TMZ to glioma poses heavy burden to glioma treatment. In this study, the effects of glioma resistance to TMZ and underlying mechanism were revealed. The expression levels of circ-VPS18, microRNA-370 (miR-370) and runt-related transcription factor 1 (RUNX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of RUNX1, multidrug resistance-associated protein 1 (MRP1), and multi-drug resistance gene-1 (MDR1) was determined by western blot. The functional effects of circ-VPS18 knockdown on TMZ sensitivity and glioma progression were revealed by cell counting kit-8 proliferation (CCK-8), flow cytometry, and transwell assays. The impacts of circ-VPS18 deletion on TMZ sensitivity in vivo were illustrated by in vivo tumor formation assay. The binding relationship between miR-370 and circ-VPS18 or RUNX1 was predicted by starBase v2.0 online database and identified by dual-luciferase reporter assay. Circ-VPS18 expression and the mRNA and protein levels of RUNX1 were dramatically upregulated, and miR-370 expression was significantly downregulated in glioma cells, TMZ-resistant glioma tissues, or tissue compared with control groups. Functionally, circ-VPS18 knockdown improved TMZ sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in U251/TR and LN229/TR cells, which was reversed by miR-370 inhibitor. Additionally, RUNX1 overexpression hindered the effects of miR-370 on TMZ sensitivity and glioma progression. Circ-VPS18 knockdown enhanced TMZ sensitivity in vivo. Mechanistically, circ-VPS18 functioned as a sponge of miR-370 and miR-370 targeted RUNX1. Circ-VPS18 knockdown improved TMZ sensitivity and repressed glioma progression by sponging miR-370 to downregulate RUNX1 expression, which provided a new insight in further studying glioma resistance to TMZ.

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References

  • Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2011) The brain tumor microenvironment. Glia 59:1169–1180

    Article  Google Scholar 

  • Chen F, Feng Z, Zhu J, Liu P, Yang C, Huang R, Deng Z (2018) Emerging roles of circRNA_NEK6 targeting miR-370-3p in the proliferation and invasion of thyroid cancer via Wnt signaling pathway. Cancer Biol Ther 19:1139–1152

    Article  CAS  Google Scholar 

  • D’Angelo F, Ceccarelli M, Tala GL, Zhang J, Frattini V, Caruso FP, Lewis G, Alfaro KD, Bauchet L, Berzero G, Cachia D, Cangiano M, Capelle L, de Groot J, DiMeco F, Ducray F, Farah W, Finocchiaro G, Goutagny S, Kamiya-Matsuoka C, Lavarino C, Loiseau H, Lorgis V, Marras CE, McCutcheon I, Nam D-H, Ronchi S, Saletti V, Seizeur R, Slopis J, Suñol M, Vandenbos F, Varlet P, Vidaud D, Watts C, Tabar V, Reuss DE, Kim S-K, Meyronet D, Mokhtari K, Salvador H, Bhat KP, Eoli M, Sanson M, Lasorella A, Iavarone A (2019) The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med 25:176–187

    Article  CAS  Google Scholar 

  • Gao Y-T, Chen X-B, Liu H-L (2016) Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression. Scientific reports 6:32972–32972

    Article  CAS  Google Scholar 

  • Gong W, Zheng J, Liu X, Liu Y, Guo J, Gao Y, Tao W, Chen J, Li Z, Ma J, Xue Y (2017) Knockdown of long non-coding RNA KCNQ1OT1 restrained glioma cells’ malignancy by activating miR-370/CCNE2 axis. Frontiers in cellular neuroscience 11:84–84

    Article  Google Scholar 

  • Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, Qiu X, Wang W, Li W, Yao Y, Li S, Li S, Wu A, Sai K, Bai H, Li G, Chen B, Yao K, Wei X, Liu X, Zhang Z, Dai Y, Lv S, Wang L, Lin Z, Dong J, Xu G, Ma X, Cai J, Zhang W, Wang H, Chen L, Zhang C, Yang P, Yan W, Liu Z, Hu H, Chen J, Liu Y, Yang Y, Wang Z, Wang Z, Wang Y, You G, Han L, Bao Z, Liu Y, Wang Y, Fan X, Liu S, Liu X, Wang Y, Wang Q (2016) CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 375:263–273

    Article  CAS  Google Scholar 

  • Kun-Peng Z, Xiao-Long M, Chun-Lin Z (2018) Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1. International journal of biological sciences 14:321–330

    Article  Google Scholar 

  • Lee W, Lim S, Kim Y (2017) The role of myosin II in glioma invasion: a mathematical model. PLoS one 12:e0171312–e0171312

    Article  Google Scholar 

  • Li Q, Chang Y, Mu L, Song Y (2019) MicroRNA-9 enhances chemotherapy sensitivity of glioma to TMZ by suppressing TOPO II via the NF-κB signaling pathway. Oncology letters 17:4819–4826

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S (2015) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25:981–984

    Article  CAS  Google Scholar 

  • Lie-A-Ling M, Mevel R, Patel R, Blyth K, Baena E, Kouskoff V, Lacaud G (2020) RUNX1 dosage in development and cancer. Mol Cells 43:126–138

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lv F, Zheng K, Yu J, Huang Z (2018) MicroRNA-661 expression is upregulated in pancreatic ductal adenocarcinoma and promotes cell proliferation. Oncology letters 16:6293–6298

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mevel R, Draper JE, Lie ALM, Kouskoff V, Lacaud G (2019) RUNX transcription factors: orchestrators of development. Development 146(17):dev148296

    Article  Google Scholar 

  • Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol 19:v1–v88

    Article  Google Scholar 

  • Reddy KB (2015) MicroRNA (miRNA) in cancer. Cancer Cell Int 15:38

    Article  Google Scholar 

  • Sangpairoj K, Vivithanaporn P, Apisawetakan S, Chongthammakun S, Sobhon P, Chaithirayanon K (2017) RUNX1 regulates migration, invasion, and angiogenesis via p38 MAPK pathway in human glioblastoma. Cell Mol Neurobiol 37:1243–1255

    Article  CAS  Google Scholar 

  • Shi L, Fei X, Wang Z, You Y (2015) PI3K inhibitor combined with miR-125b inhibitor sensitize TMZ-induced anti-glioma stem cancer effects through inactivation of Wnt/β-catenin signaling pathway. Vitro Cell Dev Biol Anim 51:1047–1055

    Article  CAS  Google Scholar 

  • Si W, Shen J, Zheng H, Fan W (2019) The role and mechanisms of action of microRNAs in cancer drug resistance. Clinical epigenetics 11:25–25

    Article  Google Scholar 

  • Teng H, Wang P, Xue Y, Liu X, Ma J, Cai H, Xi Z, Li Z, Liu Y (2016) Role of HCP5-miR-139-RUNX1 feedback loop in regulating malignant behavior of glioma cells. Molecular therapy : the journal of the American Society of Gene Therapy 24:1806–1822

    Article  CAS  Google Scholar 

  • Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu Y-M, Dhanasekaran SM, Engelke CG, Cao X, Robinson DR, Nesvizhskii AI, Chinnaiyan AM (2019) The landscape of circular RNA in cancer. Cell 176:869-881.e813

    Article  CAS  Google Scholar 

  • Wu H, Liu Q, Cai T, Chen Y-d, Liao F, Wang Z-f (2014) MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1. Diagnostic pathology 9:173–173

    Article  Google Scholar 

  • Yang M, Li G, Fan L, Zhang G, Xu J, Zhang J (2019) Circular RNA circ_0034642 elevates BATF3 expression and promotes cell proliferation and invasion through miR-1205 in glioma. Biochem Biophys Res Commun 508:980–985

    Article  CAS  Google Scholar 

  • Zhang S, Cheng J, Quan C, Wen H, Feng Z, Hu Q, Zhu J, Huang Y, Wu X (2020) circCELSR1 (hsa_circ_0063809) contributes to paclitaxel resistance of ovarian cancer cells by regulating FOXR2 expression via miR-1252. Molecular therapy Nucleic acids 19:718–730

    Article  CAS  Google Scholar 

  • Zhao Z, Ji M, Wang Q, He N, Li Y (2019) Circular RNA Cdr1as upregulates SCAI to suppress cisplatin resistance in ovarian cancer via miR-1270 suppression. Molecular therapy Nucleic acids 18:24–33

    Article  CAS  Google Scholar 

  • Zhou S, Wei J, Wang Y, Liu X (2020) Cisplatin resistance-associated circRNA_101237 serves as a prognostic biomarker in hepatocellular carcinoma. Experimental and therapeutic medicine 19:2733–2740

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Central Neurosurgery Group of Encephalopath, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, 130021, Changchun, Jilin, China

    Weimin Li

  2. Department of Brain Disease Rehabilitation, Zaozhuang Hospital, Beijing University of Traditional Chinese Medicine, Zaozhuang, 277000, Shandong, China

    Qingqin Ma

  3. Department of Radiotherapy, The 80Th Group Army Hospital of Chinese PLA, Weifang, 261021, Shandong, China

    Quan Liu

  4. Department of Neurology, Provincial Hospital, Shandong First Medical University, Jinan, 250021, Shandong, China

    Peng Yan

  5. Department of Neurology, 521 Hospital of Norinco Group, Xi’an, 710000, Shaanxi, China

    Xin Wang

  6. Department of Neurology, The 985th Hospital of Chinese PLA, 030001, Taiyuan, China

    Xiaojun Jia

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  1. Weimin Li
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  2. Qingqin Ma
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  3. Quan Liu
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  4. Peng Yan
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  5. Xin Wang
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  6. Xiaojun Jia
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Contributions

Weimin Li designed and performed the research; Qingqin Ma, Quan Liu, Peng Yan, Xin Wang, and Xiaojun Jia analyzed the data; Weimin Li wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiaojun Jia.

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The authors declare that they have no conflicts of interest.

Ethics Approval and Consent to Participate

The Ethics Committee of Affiliated Hospital of Changchun University of Traditional Chinese Medicine consented this experiment. Glioma patients related to this experiment agreed with the written informed consents.

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Li, W., Ma, Q., Liu, Q. et al. Circ-VPS18 Knockdown Enhances TMZ Sensitivity and Inhibits Glioma Progression by MiR-370/RUNX1 Axis. J Mol Neurosci 71, 1234–1244 (2021). https://doi.org/10.1007/s12031-020-01749-8

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  • DOI: https://doi.org/10.1007/s12031-020-01749-8

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