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AK3 as a Hypoxia-Angiogenesis-Related Prognostic Biomarker and Therapeutic Target in Clear Cell Renal Cell Carcinoma
Dandan Zhou1, Mengzhuo Zheng2, Di Cui3
1Urology Surgery, Fuyang Normal University Affiliated First Hospital, Fuyang, Anhui, People's Republic of China.
Background:
Clear cell renal cell carcinoma is driven by hypoxia adaptation and pathological angiogenesis mediated by VHL inactivation and HIF signaling. Current treatments including VEGF-targeted therapy and immune checkpoint blockade often face resistance or inadequate response, highlighting the need for new biomarkers linked to tumor metabolism and therapy sensitivity.
Methods:
A comprehensive machine learning approach was combined with Weighted Gene Co-Expression Network Analysis of TCGA and single-cell datasets to identify hypoxia- and angiogenesis-related prognostic genes. Among them, AK3 was selected for functional validation in ccRCC tissues and cell lines, with mechanistic studies performed in vitro and in vivo.
Results:
AK3 was significantly downregulated in ccRCC and associated with poor prognosis. AK3 overexpression inhibited tumor cell proliferation and migration by suppressing PI3K/AKT/GSK3β signaling and reduced tumor progression in nude mice. Furthermore, AK3 enhanced oxaliplatin sensitivity by increasing reactive oxygen species and reducing lipid droplet accumulation, implicating its role in metabolic and redox regulation.
Conclusion:
AK3 functions as a hypoxia-angiogenesis-related tumor suppressor in ccRCC, linking energy metabolism to therapeutic response. AK3 expression may serve as a prognostic biomarker and a predictor of chemotherapy sensitivity, providing a basis for future stratified treatment or combination therapy strategies in ccRCC.
Insights
Adenosine kinase 3 (AK3) acts as a tumor suppressor in clear cell renal cell carcinoma (ccRCC). Lower AK3 levels correlate with poor prognosis and reduced chemotherapy sensitivity, suggesting AK3 as a potential biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Clear cell renal cell carcinoma (ccRCC) pathogenesis involves hypoxia adaptation, angiogenesis, VHL inactivation, and HIF signaling.
- Current therapies like VEGF inhibitors and immune checkpoint blockade show limited efficacy due to resistance.
- Novel biomarkers are needed to understand ccRCC metabolism and predict treatment response.
Purpose of the Study:
- Identify novel prognostic genes related to hypoxia and angiogenesis in ccRCC.
- Validate the functional role of AK3 in ccRCC progression and therapeutic sensitivity.
Main Methods:
- Utilized machine learning and Weighted Gene Co-Expression Network Analysis on TCGA and single-cell datasets.
- Performed functional validation of AK3 in ccRCC tissues and cell lines.
- Conducted in vitro and in vivo mechanistic studies to elucidate AK3 function.
Main Results:
- AK3 was significantly downregulated in ccRCC and associated with poor prognosis.
- AK3 overexpression suppressed tumor cell proliferation, migration, and progression by inhibiting PI3K/AKT/GSK3β signaling.
- AK3 enhanced oxaliplatin sensitivity by modulating reactive oxygen species and lipid metabolism.
Conclusions:
- AK3 functions as a hypoxia-angiogenesis-related tumor suppressor in ccRCC.
- AK3 links tumor metabolism and redox regulation to therapeutic response.
- AK3 expression may serve as a prognostic biomarker and predict chemotherapy sensitivity for ccRCC treatment strategies.
