Abstract
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.
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Data Availability
The datasets used and analyzed during the current study are available on the GEO database.
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WW, SH, WG, YF, KL, and DW, designed the study. WW, SH, WG, YF, KL, and DW performed the experiments. WW, KL, and DW performed the statistical analysis. WW, SH, and DW wrote the manuscript. WW and DW reviewed and edited the manuscript. All authors read and approved the final manuscript.
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Wang, W., Han, S., Gao, W. et al. Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From miR-761. Cell Mol Neurobiol 42, 695–708 (2022). https://doi.org/10.1007/s10571-020-00958-4
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DOI: https://doi.org/10.1007/s10571-020-00958-4