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ZBED6-IGF2-PIK3C3 autophagy axis drives ccRCC progression: A multi-omics integration study
Xiaochen Qi1, Guandu Li1, Yuanxin Liu1
1Department of Urology, First Affiliated Hospital of Dalian Medical Universiy, No.222 Zhongshan Road, Xigang District, Dalian, Liaoning Province, China.
Abstract:
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, we identify a regulatory axis wherein the transcription factor ZBED6 activates the expression of the autophagy-initiating kinase PIK3C3 via the repression of IGF2, thereby driving pro-tumorigenic autophagy. Spatial analysis confirms the co-localization of ZBED6 and PIK3C3 in tumor tissues. Using genes associated with this axis, we develop a six-gene prognostic signature that stratifies patients with distinct survival outcomes and differential responses to immunotherapy and targeted therapy. Functional assays show that ZBED6 promotes ccRCC cell proliferation, migration, and invasion. This work elucidates a pathway governing autophagy in ccRCC and provides a framework for prognostic assessment and precision therapy.
Insights
This study reveals how ZBED6 drives kidney cancer progression by activating autophagy through PIK3C3. This finding offers new targets for clear cell renal cell carcinoma (ccRCC) therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Autophagy is crucial for clear cell renal cell carcinoma (ccRCC) progression.
- The upstream regulators of autophagy in ccRCC are not fully understood.
Purpose of the Study:
- To identify the regulatory mechanisms controlling autophagy in ccRCC.
- To explore the role of ZBED6 in ccRCC pathogenesis.
- To develop a prognostic signature for ccRCC patients.
Main Methods:
- Integration of bulk, single-cell, and spatial transcriptomics.
- Spatial analysis of ZBED6 and PIK3C3 co-localization.
- Development of a six-gene prognostic signature.
- Functional assays to assess ZBED6's role in ccRCC cell behavior.
Main Results:
- Identified a ZBED6-PIK3C3 axis that activates pro-tumorigenic autophagy via IGF2 repression.
- Confirmed ZBED6 and PIK3C3 co-localization in ccRCC tissues.
- Developed a six-gene signature predicting patient survival and therapy response.
- Demonstrated that ZBED6 enhances ccRCC cell proliferation, migration, and invasion.
Conclusions:
- Elucidated a novel pathway regulating autophagy in ccRCC.
- The ZBED6-PIK3C3 axis is a key driver of ccRCC progression.
- The six-gene signature offers a framework for prognostic assessment and precision therapy in ccRCC.
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