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TRAF7 knockdown induces cellular senescence and synergizes with lomustine to inhibit glioma progression and
Yu Chen1,2,3,4, Tongyu Zhou5, Rongrong Zhou1,2
1Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Background:
The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown.
Methods:
TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays.
Results:
High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth.
Conclusion:
TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.
Insights
High TRAF7 expression predicts glioma recurrence and poor survival. Targeting TRAF7 with lomustine enhances glioma treatment by inducing senescence and cell cycle arrest, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioma progression and recurrence are critical prognostic factors.
- The role and mechanism of TRAF7 in glioma remain unclear.
Purpose of the Study:
- To investigate the therapeutic role and mechanism of TRAF7 in glioma.
- To explore TRAF7 as a predictive biomarker and therapeutic target.
Main Methods:
- Analyzed TRAF7 RNA-seq in TCGA and CGGA databases.
- Assessed TRAF7 expression, senescence, and cell cycle pathways via RT-qPCR, western blotting, and IHC.
- Investigated TRAF7-KLF4 interaction using Co-IP and evaluated TRAF7 combined with lomustine in vitro, in vivo, and patient-derived glioma stem cells (GSCs).
Main Results:
- High TRAF7 expression correlates with higher recurrence rates and poorer overall survival (OS).
- TRAF7 knockdown inhibited glioma cell proliferation, invasion, and migration, activating senescence and cell cycle arrest pathways.
- Combination of TRAF7 inhibition and lomustine synergistically enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest.
- TRAF7 interacts with KLF4, and KLF4 overexpression reversed TRAF7 depletion effects.
Conclusions:
- TRAF7 serves as a predictive biomarker and potential therapeutic target for glioma progression and recurrence.
- Lomustine, by regulating senescence and cell cycle, is a priority treatment for high TRAF7-expressing gliomas.
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