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High levels of TIMP1 are associated with increased extracellular matrix stiffness in isocitrate dehydrogenase 1-wild type gliomas


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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Fig. 1: IDH-WT gliomas showed increased stiffness compared to IDH-Mut gliomas.
Fig. 2: TIMP1 was highly expressed in IDH-WT gliomas and predicted poor prognosis.
Fig. 3: TIMP1 is positively correlated with tissue stiffness and stiffness-related molecules.
Fig. 4: High expression of TIMP1 affects the tissue stiffness in glioma orthotopic xenografts.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials.


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This research was supported by grants from the National Natural Science Foundation of China (81703012, 81902548), and Science and Technology Innovation Project of Chongqing Science and Technology Commission (cstc2017jcyj-yszxX0012).

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Authors and Affiliations



Conception and design: X.-W.B., Y.-F.P., and Y.S. Cell culture: C.-H.L. Staining: C.-H.L., Y.-Q.L., M.L., and J.-Y.M. Immune blotting: C.-H.L., W.-Y.W., H.Z., L.L. Animal experiments: C.-H.L. and M.M. MS-PCR: Q.L. Data analysis: C.C., Q.N., Z.-X.Y., K.-D.Y., and X.-N.Z. Writing of the manuscript: C.-H.L., Y.-F.P., and Y.S.

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Correspondence to Xiu-Wu Bian or Yi-Fang Ping.

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The authors declare no competing interests.

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The stiffness of human glioma section measuring and human glioma section staining was approved by the Ethics Committees of Southwest Hospital (KY2021041). The animal use was approved by the Ethics Committees of Southwest Hospital (AMUWEC20210594).

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Luo, CH., Shi, Y., Liu, YQ. et al. High levels of TIMP1 are associated with increased extracellular matrix stiffness in isocitrate dehydrogenase 1-wild type gliomas. Lab Invest (2022).

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