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Circadian rhythm related genes signature in glioma for drug resistance prediction: a comprehensive analysis
Junbo Liao1,2,3, Yingxing Duan4, Xiangwang Xu1,2,3
1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Background:
Gliomas, 24% of all primary brain tumors, have diverse histology and poor survival rates, with about 70% recurring due to acquired or de novo resistance. Insomnia in patients is correlated strongly with circadian rhythm disruptions. The correlation between circadian rhythm disorders and drug resistance of some tumors has been proved. However, the precise mechanism underlying the relationship between glioma and circadian rhythm disorders has not been elucidated.
Methods:
Circadian rhythm-related genes (CRRGs) were identified using the least absolute shrinkage and selection operator (LASSO) regression, and stochastic gradient descent (SGD) was performed to form a circadian rhythm-related score (CRRS) model. The studies of immune cell infiltration, genetic variations, differential gene expression pattern, and single cell analysis were performed for exploring the mechanisms of chemotherapy resistance in glioma. The relationship between CRRGs and chemosensitivity was also confirmed by IC 50 (half maximal inhibitory concentration) analysis.
Result:
Signatures of 16 CRRGs were screened out and identified. Based on the CRRS model, an optimal comprehensive nomogram was created, exhibiting a favorable potential for predicting drug resistance in samples. Immune infiltration, cell-cell communication, and single cell analysis all indicated that high CRRS group was closely related to innate immune cells. IC50 analysis showed that CRRG knockdown enhanced the chemosensitivity of glioma.
Conclusion:
A significant correlation between CRRGs, drug resistance of glioma, and innate immune cells was found, which might hold a significant role in the drug resistance of glioma.
Insights
Circadian rhythm-related genes (CRRGs) are linked to glioma drug resistance. Targeting these genes may improve chemotherapy effectiveness by influencing innate immune cells.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Genetics
Background:
- Gliomas represent 24% of primary brain tumors, characterized by diverse histology and poor prognoses.
- High recurrence rates (70%) in gliomas are attributed to acquired or de novo resistance.
- Disruptions in circadian rhythms, often linked to insomnia, are increasingly associated with tumor drug resistance, though mechanisms in glioma remain unclear.
Purpose of the Study:
- To elucidate the precise mechanisms linking circadian rhythm disorders and glioma drug resistance.
- To identify circadian rhythm-related genes (CRRGs) associated with glioma chemoresistance.
- To explore the role of CRRGs in immune cell infiltration and their impact on treatment outcomes.
Main Methods:
- Utilized LASSO regression and SGD to identify CRRGs and develop a circadian rhythm-related score (CRRS) model.
- Conducted analyses of immune cell infiltration, genetic variations, gene expression patterns, and single-cell data.
- Assessed the relationship between CRRGs and chemosensitivity using IC50 analysis.
Main Results:
- Identified signatures of 16 CRRGs and developed a nomogram based on the CRRS model for predicting drug resistance.
- Found that a high CRRS group is strongly associated with innate immune cells, as indicated by immune infiltration and single-cell analyses.
- Demonstrated that knockdown of CRRGs enhances glioma chemosensitivity, as confirmed by IC50 analysis.
Conclusions:
- Established a significant correlation between CRRGs, glioma drug resistance, and innate immune cells.
- Suggests that CRRGs play a crucial role in the development of glioma drug resistance.
- Highlights potential therapeutic strategies targeting CRRGs to overcome chemoresistance in glioma.
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