Work

Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells

Year: 2025

Type: article

Abstract: Clear cell renal cell carcinoma (ccRCC), accounting for 80-90% of renal malignancies, is frequently driven by VHL inactivation-either through mutation or promoter hypermethylation-resulting in constitutive HIF2α activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel-Lindau syndrome, a hereditary disorder predisposing patients to ccRCC and other tumors, underscoring its central role in disease pathogenesis. While VHL dysfunction promotes aggressive tumor phenotypes, the therapeutic potential of VHL restoration remains underexplored. Here, using the Cas9 induced VHL-mutation in the Caki-1 cell line model, we demonstrate that VHL inactivation augments hypoxia-like pathways and enhances anaerobic glycolysis. Rescue of functional VHL reversed these activation patterns and modulated the expression of genes associated with angiogenesis. Using single cell transcriptomics, we show that the VHL-positive and -negative Caki-1 cells are characterized with different proportions of benign and aggressive cells as seen by analysis of specific gene expression. Furthermore, the identified angiogenesis-related genes were linked to affect clinical outcomes in ccRCC patients, suggesting that VHL restoration may mitigate high-risk molecular features.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms262110629

Authors: Pavel Abramov, Alexandr Mazur, Aleksey Starshin, Svetlana Zhenilo, Egor Prokhortchouk

Institutions: Russian Academy of Sciences, Federal Research Centre «Fundamentals of Biotechnology» of the Russian Academy of Sciences, Institute of Gene Biology, Sirius University of Science and Technology

Language: English

Topic: Cancer, Hypoxia, and Metabolism

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499