Glioma–astrocyte connexin43 confers temozolomide resistance through activation of the E2F1/ERCC1 axis

替莫唑胺 胶质瘤 ERCC1公司 星形胶质细胞 E2F1 癌症研究 胶质母细胞瘤 医学 内科学 生物 癌症 中枢神经系统 遗传学 细胞周期 DNA修复 核苷酸切除修复 基因
作者
Yanping Gui,Hongkun Qin,Xinyu Zhang,Qianqian Chen,Fangyu Ye,Tian Geng,Shihe Yang,Yuting Ye,Di Pan,Jieying Zhou,Xiangshan Fan,Yajing Wang,Li Zhao
出处
期刊:Neuro-oncology [Oxford University Press]
卷期号:27 (3): 711-726 被引量:3
标识
DOI:10.1093/neuonc/noae237
摘要

Abstract Background Glioma is the most prevalent and lethal tumor of the central nervous system. Routine treatment with temozolomide (TMZ) would unfortunately result in inevitable recurrence and therapy resistance, severely limiting therapeutic efficacy. Tumor-associated astrocytes (TAAs) are key components of the tumor microenvironment and increasing evidence has demonstrated that aberrant expression of connexin43 (Cx43) was closely associated with glioma progression and TMZ resistance. However, the specific role of Cx43 in mediating TMZ resistance through glioma and astrocyte interactions has not been fully explored. Methods The expression and prognostic value of Cx43 were evaluated in tumor samples and clinical databases. ShRNA-medicated knockdown and Gfap-Cre Cx43flox/flox gene mouse were used to assess the role and functional significance of Cx43 in vitro and in vivo. Moreover, we performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which Cx43 promotes TMZ resistance. Results We confirmed that the upregulation of Cx43 expression between TAAs and glioma cells contributed to TMZ resistance and tumor recurrence. Genetic knockdown or pharmacological inhibition of Cx43 enhanced TMZ-induced cytotoxicity. Mechanistically, elevated Cx43 expression induced β-catenin accumulation at the cell surface of glioma cells, suppressing T-cell factor/lymphoid enhancer-binding factor transcription. This led to impaired miR-205-5p expression and subsequent activation of the E2F1/ERCC1 axis, which eventually led to chemoresistance. Conclusions Our study reveals a novel regulatory mechanism in which the Cx43/miR-205-5p/E2F1/ERCC1 axis contributes to TMZ resistance in glioma. These findings further highlight the potential of targeting Cx43 as a therapeutic strategy in glioma.
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