{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:30:10Z","timestamp":1762349410023,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-74-30026"],"award-info":[{"award-number":["19-74-30026"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u00abSirius\u00bb Federal Territory \u00abScientific and Technological Development of the \u00abSirius\u00bb Federal Territory\u00bb","award":["21-03"],"award-info":[{"award-number":["21-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clear cell renal cell carcinoma (ccRCC), accounting for 80\u201390% of renal malignancies, is frequently driven by VHL inactivation\u2014either through mutation or promoter hypermethylation\u2014resulting in constitutive HIF2\u03b1 activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel\u2013Lindau 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.<\/jats:p>","DOI":"10.3390\/ijms262110629","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"10629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-3490","authenticated-orcid":false,"given":"Pavel","family":"Abramov","sequence":"first","affiliation":[{"name":"Federal Research Centre \u00abFundamentals of Biotechnology\u00bb, Russian Academy of Sciences, 119071 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandr","family":"Mazur","sequence":"additional","affiliation":[{"name":"Federal Research Centre \u00abFundamentals of Biotechnology\u00bb, Russian Academy of Sciences, 119071 Moscow, Russia"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4965-0165","authenticated-orcid":false,"given":"Aleksey","family":"Starshin","sequence":"additional","affiliation":[{"name":"Federal Research Centre \u00abFundamentals of Biotechnology\u00bb, Russian Academy of Sciences, 119071 Moscow, Russia"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-1594","authenticated-orcid":false,"given":"Svetlana","family":"Zhenilo","sequence":"additional","affiliation":[{"name":"Federal Research Centre \u00abFundamentals of Biotechnology\u00bb, Russian Academy of Sciences, 119071 Moscow, Russia"},{"name":"Group of Epigenetic Editing, Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, 354340 Sirius, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8234-9975","authenticated-orcid":false,"given":"Egor","family":"Prokhortchouk","sequence":"additional","affiliation":[{"name":"Federal Research Centre \u00abFundamentals of Biotechnology\u00bb, Russian Academy of Sciences, 119071 Moscow, Russia"},{"name":"Group of Epigenetic Editing, Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, 354340 Sirius, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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