Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From
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ORIGINAL RESEARCH
Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From miR‑761 Wei Wang1 · Shuai Han1 · Wei Gao1 · Yuan Feng1 · Kunhang Li1 · Di Wu2 Received: 7 April 2020 / Accepted: 30 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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 TMZinduced 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 KCNQ1OT1 · miR-761 · PIM1 · Glioma · Temozolomide resistance · Growth
Introduction Glioma, the most prevalent histological type of primary central nervous system cancer, is one of the fatal cancers in humans (Brain and Other CNSCC 2019). The present comprehensive treatment includes surgical resection, radiotherapy, and chemotherapy, among which temozolomide Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00958-4) contains supplementary material, which is available to authorized users. * Di Wu [email protected] 1
Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People’s Republic of China
Department of Tumor Biotherapy and Cancer Research, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People’s Republic of China
2
(TMZ) is the most effective chemical agent. TMZ significantly improved the survival period and the quality of life combined with radiation therapy (Jiapaer et al. 2018); however, the increment of TMZ resistance led to glioma treatment frustration. At present, researchers illustrated that DNA repair systems, autoph
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