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m7G regulator-mediated molecular subtypes and tumor microenvironment in kidney renal clear cell carcinoma
Mei Chen1, Zhenyu Nie1, Yuanhui Gao1
1Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China.
Abstract:
Background: RNA methylation modification plays an important role in immune regulation. m7G RNA methylation is an emerging research hotspot in the RNA methylation field. However, its role in the tumor immune microenvironment of kidney renal clear cell carcinoma (KIRC) is still unclear. Methods: We analyzed the expression profiles of 29 m7G regulators in KIRC, integrated multiple datasets to identify a novel m7G regulator-mediated molecular subtype, and developed the m7G score. We evaluated the immune tumor microenvironments in m7G clusters and analyzed the correlation of the m7G score with immune cells and drug sensitivity. We tested the predictive power of the m7G score for prognosis of patients with KIRC and verified the predictive accuracy of the m7G score by using the GSE40912 and E-MTAB-1980 datasets. The genes used to develop the m7G score were verified by qRT-PCR. Finally, we experimentally analyzed the effects of WDR4 knockdown on KIRC proliferation, migration, invasion, and drug sensitivity. Results: We identified three m7G clusters. The expression of m7G regulators was higher in cluster C than in other clusters. m7G cluster C was related to immune activation, low tumor purity, good prognosis, and low m7G score. Cluster B was related to drug metabolism, high tumor purity, poor survival, and high m7G score. Cluster A was related to purine metabolism. The m7G score can well-predict the prognosis of patients with KIRC, and its prediction accuracy based on the m7G score nomogram was very high. Patients with high m7G scores were more sensitive to rapamycin, gefitinib, sunitinib, and vinblastine than other patients. Knocking down WDR4 can inhibit the proliferation, migration, and invasion of 786-0 and Caki-1 cells and increase sensitivity to sorafenib and sunitinib. Conclusion: We proposed a novel molecular subtype related to m7G modification and revealed the immune cell infiltration characteristics of different subtypes. The developed m7G score can well-predict the prognosis of patients with KIRC, and our research provides a basis for personalized treatment of patients with KIRC.
Insights
This study identifies novel molecular subtypes in kidney renal clear cell carcinoma (KIRC) based on m7G RNA methylation regulators. The developed m7G score predicts patient prognosis and guides personalized treatment strategies for KIRC.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- RNA methylation, specifically m7G modification, is crucial for immune regulation and an active research area.
- The role of m7G RNA methylation in the tumor immune microenvironment of kidney renal clear cell carcinoma (KIRC) remains largely unexplored.
- Understanding these mechanisms is vital for advancing KIRC treatment strategies.
Purpose of the Study:
- To investigate the role of m7G RNA methylation regulators in KIRC.
- To identify novel m7G regulator-mediated molecular subtypes within KIRC.
- To develop and validate an m7G score for predicting patient prognosis and guiding personalized therapy.
Main Methods:
- Analysis of expression profiles for 29 m7G regulators in KIRC datasets.
- Integration of multiple datasets to define m7G-mediated molecular subtypes and develop the m7G score.
- Evaluation of tumor immune microenvironments, immune cell infiltration, and drug sensitivity across subtypes.
- Validation of the m7G score's predictive accuracy using independent KIRC datasets (GSE40912, E-MTAB-1980).
- Experimental validation of key genes (WDR4) using qRT-PCR and cell line studies (proliferation, migration, invasion, drug sensitivity).
Main Results:
- Three distinct m7G clusters were identified, with Cluster C showing higher m7G regulator expression, immune activation, low tumor purity, and good prognosis.
- Cluster B was associated with drug metabolism, high tumor purity, poor survival, and a high m7G score.
- The m7G score demonstrated high accuracy in predicting KIRC patient prognosis and identified patient subgroups sensitive to specific drugs (rapamycin, gefitinib, sunitinib, vinblastine).
- Knockdown of WDR4 inhibited KIRC cell proliferation, migration, and invasion, while increasing sensitivity to sorafenib and sunitinib.
Conclusions:
- A novel molecular subtype associated with m7G modification in KIRC was identified, revealing distinct immune cell infiltration characteristics.
- The developed m7G score serves as a robust predictor of prognosis for KIRC patients.
- This research provides a foundation for personalized treatment approaches in KIRC based on m7G modification status.
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