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Multi-omics analysis reveals CLIC1 as a therapeutic vulnerability of gliomas
1Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China.
Abstract:
Introduction: Despite advances in comprehending cancer biology, malignant gliomas remain incurable. The present work conducted a multi-omics analysis for investigating the significance of chloride intracellular channel 1 (CLIC1) in gliomas. Methods: Multi-omics data of glioma covering transcriptomics, genomics, DNA methylation and single-cell transcriptomics from multiple public cohorts were enrolled for analyzing CLIC1. In vitro experiments were conducted to measure apoptosis and cell mobility in U251 and U373 glioma cells following transfection of CLIC1 siRNAs. Results: Elevated CLIC1 expression was proven to stably and independently estimate worse survival outcomes. CLIC1 expression was higher in more advanced stage, wild-type IDH and unmethylated MGMT samples. Tumorigenic and anticancer immunity pathways were remarkably enriched in CLIC1-up-regulated tumors. Additionally, CLIC1 was positively linked with cancer-immunity cycle, stromal activation, DNA damage repair and cell cycle. Suppressing CLIC1 resulted in apoptosis and attenuated cell motility of glioma cells. More frequent genomic alterations were found in CLIC1-up-regulated tumors. CLIC1 expression presented a remarkably negative connection to DNA methylation. High CLIC1 expression samples were more sensitive to camptothecin, cisplatin, doxorubicin, erlotinib, paclitaxel, rapamycin, clofarabine, tanespimycin, methotrexate, everolimus, TAK-733, trametinib and AZD8330. Tumors with upregulated CLIC1 presented abundant immune cell infiltration, higher expression of immune-checkpoints and -modulators and similar transcriptome profiling, indicative of well response to immune-checkpoint blockade (ICB). Nevertheless, due to elevated TIDE score, tumors with CLIC1 upregulation appeared to be resistant to ICB. Single-cell analysis unveiled that CLIC1 was expressed ubiquitously in tumor cells and tumor microenvironment. Conclusions: Overall, CLIC1 was a promising treatment vulnerability in glioma.
Insights
Chloride intracellular channel 1 (CLIC1) is a promising target in glioma treatment. Suppressing CLIC1 induces apoptosis and reduces cell motility, indicating its potential as a therapeutic vulnerability.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Malignant gliomas remain incurable despite advances in cancer biology.
- Understanding molecular drivers is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role and significance of chloride intracellular channel 1 (CLIC1) in glioma using multi-omics analysis.
- To explore CLIC1 as a potential therapeutic vulnerability in glioma.
Main Methods:
- Multi-omics data analysis (transcriptomics, genomics, DNA methylation, single-cell transcriptomics) from public glioma cohorts.
- In vitro experiments assessing apoptosis and cell motility in glioma cells after CLIC1 siRNA transfection.
Main Results:
- Elevated CLIC1 expression correlates with worse survival, advanced stage, and specific molecular subtypes (wild-type IDH, unmethylated MGMT).
- CLIC1 is linked to tumorigenesis, immune response pathways, DNA repair, and cell cycle regulation; its suppression induces apoptosis and reduces cell motility.
- High CLIC1 expression suggests sensitivity to certain chemotherapies and targeted agents, but potential resistance to immune-checkpoint blockade (ICB) despite increased immune infiltration.
Conclusions:
- CLIC1 is a significant molecular marker in glioma, associated with aggressive features and therapeutic response.
- CLIC1 represents a promising therapeutic vulnerability for glioma treatment, warranting further investigation.
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