Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
Lab Invest. 2022 Dec;102(12):1304-1313. doi: 10.1038/s41374-022-00825-4. Epub 2022 Jul 26.
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.
胶质母细胞瘤的进展伴随着肿瘤组织硬度的增加，但潜在的机制尚不清楚。在此，我们采用原子力显微镜分析表明，异柠檬酸脱氢酶（IDH）野生型胶质瘤的组织硬度高于 IDH 突变型胶质瘤。生物信息学分析显示，组织抑制剂金属蛋白酶-1（TIMP1）是 IDH 野生型胶质瘤中优先上调的基因之一，与 IDH 突变型胶质瘤相比，其表达水平更高，提示胶质母细胞瘤患者预后较差。免疫荧光染色测定的 TIMP1 强度与胶质瘤组织硬度呈正相关。在机制上，TIMP1 表达与两种主要细胞外基质成分（纤连蛋白和 tenascin C）的基因表达呈正相关，这两种成分在 IDH 野生型胶质瘤中也高度表达。通过将含有 IDH1-R132H 的载体引入人 IDH1 野生型胶质瘤细胞中，获得 IDH1 突变细胞系，我们发现 IDH1 突变通过甲基化特异性 PCR 增加了 TIMP1 启动子的甲基化。更重要的是，与 IDH1 野生型相比，IDH1-R132H 突变降低了 IDH1 突变型胶质瘤异种移植瘤中 TIMP1、纤连蛋白和 tenascin C 的表达以及肿瘤组织硬度。此外，IDH 野生型胶质瘤细胞中 TIMP1 的敲低抑制了 tenascin C 和纤连蛋白的表达，并降低了颅内胶质瘤异种移植瘤的组织硬度。综上所述，我们揭示了一种 IDH 突变状态介导的机制，通过调节 TIMP1 和下游细胞外基质成分来调节胶质瘤组织硬度。
