时间1
胶质瘤
异柠檬酸脱氢酶
藤黄蛋白C
Tenascin公司
癌症研究
生物
细胞外基质
纤维连接蛋白
分子生物学
IDH1
化学
突变体
基因表达
细胞生物学
生物化学
基因
酶
作者
Chao Luo,Yu Shi,Yuqi Liu,Qing Liu,Min Mao,Min Luo,Kai‐Di Yang,Wenying Wang,Cong Chen,Qin Niu,Zexuan Yan,Jingya Miao,Xiaoning Zhang,Hui Zeng,Lei Li,Xiu‐Wu Bian,Yi‐Fang Ping
标识
DOI:10.1038/s41374-022-00825-4
摘要
Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.
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