Abstract: TH-PO1148
Complement C3 Is a Hypoxia-Inducible Gene Associated with Poor Prognosis in Hospitalized Patients with Kidney Cancer and New Dialysis Requirement
Session Information
- Onconephrology: Emerging Biomarkers, Preclinical Models, Clinical Challenges, and Therapeutic Strategies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Akilesh, Shreeram, University of Washington, Seattle, Washington, United States
- Miller, Chris P., Fred Hutchinson Cancer Center, Seattle, Washington, United States
- Carter, Jason A., University of Washington, Seattle, Washington, United States
- Stanaway, Ian Byrell, University of Washington, Seattle, Washington, United States
- Li, Xianwu, University of Washington, Seattle, Washington, United States
- Beirne, Emily, University of Washington, Seattle, Washington, United States
- Mills, Bre Alexis, University of Washington, Seattle, Washington, United States
- Che, Felicia, University of Washington, Seattle, Washington, United States
- Funnell, Alister P., Altius Institute for Biomedical Sciences, Seattle, Washington, United States
- Smith, Kelly D., University of Washington, Seattle, Washington, United States
- Pillarisetty, Venu, University of Washington, Seattle, Washington, United States
- Zhang, Yuzhou, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Smith, Richard J., University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Bhatraju, Pavan K., University of Washington, Seattle, Washington, United States
- Blosser, Christopher D., University of Washington, Seattle, Washington, United States
Background
C3 is the central component of the complement cascade and a major circulating serum protein produced by the liver and kidney. C3 can be induced by inflammatory stimuli, including with conditions causing hypoxia such as cancer, sepsis and hemodialysis. Yet, C3 transcriptional regulation in response to hypoxia is not well understood. Clear cell renal cell carcinoma (ccRCC) is a model system to study hypoxia responses since it displays inactivation of VHL, which suppresses hypoxia inducible factor (HIF) programs in normal oxygen conditions.
Methods
Using ccRCC as a model system, we utilized RNA in situ hybridization and spatial transcriptomics (GeoMx, CosMx) to measure C3 expression and correlated it with hypoxic gene expression signatures compared with normal kidney tissue. We utilized functional genomic methods (DNase-seq, ChIP-seq) to study regulation at the C3 genomic locus. We tested the regulation of C3 expression using genome editing, genetic complementation and chemical hypoxia. Using aptamer technology, we measured urine C3 protein levels in hospitalized patients to assess their risk of requiring dialysis.
Results
Across publicly available and newly generated datasets, we demonstrate that C3 is upregulated in cells exhibiting a hypoxic gene expression signature. Functional genomic analysis identified a HIF-bound enhancer that correlates with C3 expression. Deletion of this enhancer or VHL overexpression suppresses C3 levels (Fig. A, B). Conversely, chemical hypoxia of proximal tubule cells stimulates C3 expression (Fig. C). Higher urine C3 protein levels are associated with increased risk of dialysis requirement in hospitalized patients. Increased C3 levels are correlated with higher grade and poorer overall survival in ccRCC patients.
Conclusion
We demonstrate the mechanism by which hypoxia induces C3 expression in normal and malignant cells. Tissue hypoxia in normal and malignant tissues can induce C3, which can contribute to tissue injury and tumor growth. This study calls for investigation of whether complement pathways inhibitors may be used to treat patients with cancer or acute kidney injury.
Funding
- Private Foundation Support