Exosomal circ-HIPK3 Facilitates Tumor Progression and Temozolomide Resistance by Regulating miR-421/ ZIC5 Axis in Glioma.

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  • Author(s): Han C;Han C; Wang S; Wang S; Wang H; Wang H; Zhang J; Zhang J
  • Source:
    Cancer biotherapy & radiopharmaceuticals [Cancer Biother Radiopharm] 2021 Sep; Vol. 36 (7), pp. 537-548. Date of Electronic Publication: 2020 Jul 09.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 9605408 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8852 (Electronic) Linking ISSN: 10849785 NLM ISO Abbreviation: Cancer Biother Radiopharm Subsets: MEDLINE
    • Publication Information:
      Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c1996-
    • Subject Terms:
      Antineoplastic Agents, Alkylating/*therapeutic use ; Brain Neoplasms/*drug therapy ; Exosomes/*metabolism ; Glioma/*drug therapy ; RNA, Circular/*genetics ; Temozolomide/*therapeutic use; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Apoptosis ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Drug Resistance, Neoplasm ; Glioma/genetics ; Glioma/pathology ; Humans ; Mice ; Mice, Nude ; Temozolomide/pharmacology ; Transfection
    • Abstract:
      Background: The resistance of glioma patients to temozolomide (TMZ) treatment is a limiting factor in clinical treatment. Circular RNA HIPK3 (circ-HIPK3) was found to be highly expressed in glioma, however, the role and potential mechanism of exosomal circ-HIPK3 from TMZ-resistant cells remain poorly unclear. Methods: Exosomes were characterized by transmission electron microscopy. The levels of all protein were detected by Western blot. Expression levels of circ-HIPK3, microRNA-421 (miR-421), and zinc finger protein of the cerebellum 5 ( ZIC5 ) were measured by quantitative real-time polymerase chain reaction. The cell's 50% inhibitory concentration (IC 50 ) of TMZ, apoptosis, and invasion were determined by methyl thiazolyl tetrazolium (MTT), flow cytometry, and Transwell assays, respectively. The correlation between miR-421 and circ-HIPK3 or ZIC5 was identified by dual-reporter luciferase and RNA immunoprecipitation (RIP) assays. The xenograft model was established to explore the effect of circ-HIPK3 in vivo . Results: circ-HIPK3 was obviously increased in TMZ-resistant glioma cells and their exosomes, miR-421, was downregulated in TMZ-resistant glioma. circ-HIPK3 directly targeted miR-421 and their expressions were negatively correlated in glioma tissues. Besides, circ-HIPK3 knockdown hampered the IC 50 of TMZ, cell invasion, TMZ resistance, and triggered cell apoptosis, whereas these effects were reversed by transfection of anti-miR-421. ZIC5 was the target of miR-421 and ZIC5 overexpression weakened the inhibition effects of miR-421 on cell progression and TMZ resistance. More importantly, circ-HIPK3 depletion inhibited tumor growth by decreasing ZIC5 through sponging miR-421 in vivo . Conclusion: Exosomal circ-HIPK3 could promote cell progression and TMZ resistance by regulating miR-421/ ZIC5 axis in TMZ-resistant glioma.
    • Contributed Indexing:
      Keywords: circ-HIPK3; glioma; miR-421; temozolomide, ZIC5
    • Accession Number:
      0 (Antineoplastic Agents, Alkylating)
      0 (RNA, Circular)
      YF1K15M17Y (Temozolomide)
    • Publication Date:
      Date Created: 20200710 Date Completed: 20220128 Latest Revision: 20220128
    • Publication Date:
      20240105
    • Accession Number:
      10.1089/cbr.2019.3492
    • Accession Number:
      32644821