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Vimentin promotes glioma progression and maintains glioma cell resistance to oxidative phosphorylation inhibition

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Abstract

Purpose

Glioma has been demonstrated as one of the most malignant intracranial tumors and currently there is no effective treatment. Based on our previous RNA-sequencing data for oxidative phosphorylation (OXPHOS)-inhibition resistant and OXPHOS-inhibition sensitive cancer cells, we found that vimentin (VIM) is highly expressed in the OXPHOS-inhibition resistant cancer cells, especially in glioma cancer cells. Further study of VIM in the literature indicates that it plays important roles in cancer progression, immunotherapy suppression, cancer stemness and drug resistance. However, its role in glioma remains elusive. This study aims to decipher the role of VIM in glioma, especially its role in OXPHOS-inhibition sensitivity, which may provide a promising therapeutic target for glioma treatment.

Methods

The expression of VIM in glioma and the normal tissue has been obtained from The Cancer Genome Atlas (TCGA) database, and further validated in Human Protein Atlas (HPA) and Chinese Glioma Genome Atlas (CGGA). And the single-cell sequencing data was obtained from TISCH2. The immune infiltration was calculated via Tumor Immune Estimation Resource (TIMER), Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data (ESTIMATE) and ssGSEA, and the Immunophenoscore (IPS) was calculated via R package. The differentiated expressed genes were analyzed including GO/KEGG and Gene Set Enrichment Analysis (GSEA) between the VIM-high and -low groups. The methylation of VIM was checked at the EWAS and Methsurv. The correlation between VIM expression and cancer stemness was obtained from SangerBox. We also employed DepMap data and verified the role of VIM by knocking down it in VIM-high glioma cell and over-expressing it in VIM-low glioma cells to check the cell viability.

Results

Vim is highly expressed in the glioma patients compared to normal samples and its high expression negatively correlates with patients’ survival. The DNA methylation in VIM promoters in glioma patients is lower than that in the normal samples. High VIM expression positively correlates with the immune infiltration and tumor progression. Furthermore, Vim is expressed high in the OXPHOS-inhibition glioma cancer cells and low in the OXPHOS-inhibition sensitive ones and its expression maintains the OXPHOS-inhibition resistance.

Conclusions

In conclusion, we comprehensively deciphered the role of VIM in the progression of glioma and its clinical outcomes. Thus provide new insights into targeting VIM in glioma cancer immunotherapy in combination with the current treatment.

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Data availability

The data underlying this study are freely available from TCGA data portal (https://portal.gdc.cancer.gov/projects/TCGA-LGG). The RNA-seq raw sequence data reported in this paper has been deposited into the Genome Sequence Archive (GSA) for humans under accession: HRA001452.

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Acknowledgements

Not applicable

Funding

This study was funded by Discipline Climbing Scheme (2019YXK030) and Neuroscience Innovation and Development Research Project (YXJL-2022–00351-0183). This work was supported by grants from the National Natural Science Foundation of China (82073274, Y.S.), Science Technology Commission of Shanghai Municipality (20S11900700, Y.S.).

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Author notes

  1. Yu’e Liu and Shu Zhao contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China

    Yu’e Liu, Shu Zhao, Le He, Jie Chen & Kaijun Zhao

  2. The China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China

    Yi Chen

  3. Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China

    Wencong Ma

  4. Center for Translational Research in Infection and Inflammation, School of Medicine, Tulane University, New Orleans, LA, 70112, USA

    Shiping Lu

  5. Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    Xi Chen

  6. National Joint Engineering Laboratory for Human Disease Animal Models, Key Laboratory of Organ Regeneration and Transplantation, First Hospital of Jilin University, Changchun, China

    Xiaoling Zhang

  7. Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai, 200092, China

    Yufeng Shi

  8. Department of Oncology, Huai’an Second People’s Hospital, Affiliated to Xuzhou Medical University, Huai’an, Jiangsu, China

    Xuan Jiang

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  1. Yu’e Liu
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Contributions

K.Z and X.J conceived and designed the study. Y.L analyzed the data, did experiments and wrote the manuscript. S.Z,Y.C, W,M and L.H performed some of experiments and did partial literature sourcing. S.L, J.C, Y.S, X.C and X,Z analyzed parts of the data and sourced literature. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Xuan Jiang or Kaijun Zhao.

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Supplementary Information

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Supplementary figure 1 The expression of VIM in Chinse glioma patients (CGGA database)

(A). The expression of VIM in different histology of Chinese gliomas. (B). The expression of VIM in different pathological stages in Chinese glioma patients. (C) The expression of VIM in IDH-mutant and IDH-wild type gliomas in Chinese patients. (D). The expression of VIM in different grades in IDH-mutant and IDH-wild type gliomas in Chinese patients. (E). The expression of VIM in different genders of Chinese glioma patients. (F). The expression of VIM in different ages of Chinese glioma patients. (G). The expression of VIM in primary and recurrent gliomas of Chinese patients. (H). The expression of VIM in different stages of primary and recurrent gliomas of Chinese patients (JPG 2.22 MB)

Supplementary figure 2 Correlation between the expression of VIM and the Chinese glioma patients’ survival (CGGA database)

(A). Correlation between the expression of VIM and the Chinese glioma patients with all different grades of gliomas. (B). The correlation between the expression of VIM and the survival of primary glioma and recurrent gliomas in grade II in Chinese patients. (C). The correlation between the expression of VIM and the survival of primary glioma and recurrent gliomas in grade III in Chinese patients. (D). The correlation between the expression of VIM and the survival of primary glioma and recurrent gliomas in grade IV in Chinese patients (JPG 2.51 MB)

Supplementary figure 3 The methylation of VIM in VIM (CGGA database)

(A). The methylation of VIM of glioma patients with different histology. (B).The methylation level of VIM in different pathological stages. (C). The methylation of VIM in different genders in different stages. (D). The methylation level of VIM in glioma patients of different ages (JPG 1.34 MB)

Supplementary figure 4 The correlation between the methylation level and the patients’ survival (CGGA database)

(A). The correlation between the methylation level of VIM and patients’ survival. (B). The correlation between the methylation level of VIM and patients’ survival for patients in grade II (left) and grade III (right) stages. (C). The correlation between the methylation level of VIM and survival for patients in grade IV (JPG 2.46 MB)

Supplementary file 5

The IC50s of 57 cancer cell lines treated by Gboxin (XLSX 14.0 KB)

Supplementary file 6

ell viability of CRISPR knocking out VIM in 67 glioma cell lines, data from DepMap (XLSX 62.8 KB)

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Liu, Y., Zhao, S., Chen, Y. et al. Vimentin promotes glioma progression and maintains glioma cell resistance to oxidative phosphorylation inhibition. Cell Oncol. 46, 1791–1806 (2023). https://doi.org/10.1007/s13402-023-00844-3

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