Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From miR-761

Cell Mol Neurobiol. 2022 Apr;42(3):695-708. doi: 10.1007/s10571-020-00958-4. Epub 2020 Sep 8.


Many studies have found that the dysregulation of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling pathways. However, the underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant gliomas were not well understood, hindering the improvement of TMZ-based therapies. The present study demonstrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant glioma cells compared to the TMZ-sensitive cells. The introduction of KCNQ1OT1 promoted cell viability, clonogenicity, and rhodamine 123 efflux while hampering TMZ-induced apoptosis. Moreover, KCNQ1OT1 directly sponged miR-761, which decreased in TMZ-resistant sublines. The overexpression of miR-761 attenuated cell viability and clonogenicity, while triggering apoptosis and rhodamine 123 accumulation post-TMZ exposure, leading to a response to TMZ. The interaction between miR-761 and 3'-untranslated region of PIM1 attenuated PIM1-mediated signaling cascades. Furthermore, the knockdown of KCNQ1OT1 augmented the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated that KCNQ1OT1 conferred TMZ resistance by releasing PIM1 expression from miR-761, resulting in the upregulation of PIM-mediated MDR1, c-Myc, and Survivin. The present findings demonstrated that the interplay of KCNQ1OT1: miR-761: PIM1 regulated chemoresistance in gliomas and provided a promising therapeutic target for TMZ-resistant glioma patients.

Keywords: Glioma; Growth; KCNQ1OT1; PIM1; Temozolomide resistance; miR-761.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic
  • Glioma* / drug therapy
  • Glioma* / genetics
  • Glioma* / pathology
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • Potassium Channels, Voltage-Gated
  • Proto-Oncogene Proteins c-pim-1* / genetics
  • Proto-Oncogene Proteins c-pim-1* / metabolism
  • RNA, Long Noncoding* / genetics
  • Temozolomide* / pharmacology
  • Temozolomide* / therapeutic use


  • Antineoplastic Agents, Alkylating
  • KCNQ1OT1 long non-coding RNA, human
  • MicroRNAs
  • Potassium Channels, Voltage-Gated
  • RNA, Long Noncoding
  • microRNA761 microRNA, human
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • Temozolomide