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长链非编码 RNA MIR155HG 通过与 PTBP1 结合激活 Wnt/β-连环蛋白通路促进脑胶质瘤替莫唑胺耐药

LncRNA MIR155HG Promotes Temozolomide Resistance by Activating the Wnt/β-Catenin Pathway Via Binding to PTBP1 in Glioma.

机构信息

Institute of Neuroscience, Chongqing Medical University, Chongqing, China.

出版信息

Cell Mol Neurobiol. 2021 Aug;41(6):1271-1284. doi: 10.1007/s10571-020-00898-z. Epub 2020 Jun 11.

Abstract

Temozolomide (TMZ) is widely used for glioma therapy in the clinic. Currently, the development of TMZ resistance has largely led to poor prognosis. However, very little is understood about the role of MIR155HG, as a long noncoding RNA, in TMZ resistance. In our study, MIR155HG level was markedly higher in glioma patients than in normal controls and that poor survival was positively correlated with MIR155HG expression. It was apparent that TMZ sensitivity was promoted by downregulation of MIR155HG, and this could be reversed by MIR155HG overexpression in vivo and in vitro. Furthermore, polypyrimidine tract binding protein 1 (PTBP1) was proven to bind with MIR155HG and to regulate MIR155HG-related TMZ resistance. Mechanistic investigation showed that the expression levels of both MIR155HG and PTBP1 influenced the expression of relevant proteins in the Wnt/β-catenin pathway. Collectively, the study demonstrated that the knockdown of MIR155HG increased glioma sensitivity to TMZ by inhibiting Wnt/β-catenin pathway activation via potently downregulating PTBP1.

摘要

替莫唑胺(TMZ)在临床上广泛用于治疗脑胶质瘤。目前,TMZ 耐药性的发展在很大程度上导致了预后不良。然而,作为一种长非编码 RNA,MIR155HG 在 TMZ 耐药性中的作用知之甚少。在我们的研究中,MIR155HG 在脑胶质瘤患者中的水平明显高于正常对照,并且与 MIR155HG 表达呈正相关的不良预后。显然,下调 MIR155HG 可促进 TMZ 敏感性,并且这种作用可在体内和体外通过 MIR155HG 过表达逆转。此外,多嘧啶 tract 结合蛋白 1(PTBP1)被证明与 MIR155HG 结合,并调节 MIR155HG 相关的 TMZ 耐药性。机制研究表明,MIR155HG 和 PTBP1 的表达水平均影响 Wnt/β-catenin 通路相关蛋白的表达。总之,该研究表明,通过强烈下调 PTBP1 抑制 Wnt/β-catenin 通路激活,下调 MIR155HG 可增加脑胶质瘤对 TMZ 的敏感性。

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