{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:02:55Z","timestamp":1780578175305,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a key negative regulator of NF-\u03baB signaling with context-dependent functions in cancer. Its role in renal cell carcinoma (RCC), particularly clear-cell RCC (ccRCC), remains incompletely defined. Methods: Public GEO transcriptomic data from 23 controls and 32 ccRCC samples were analyzed using gene set enrichment analysis (GSEA). A20-overexpressing HEK293 and 786-O cells were assessed by functional assays and transcriptomic profiling. Eight ccRCC FFPE samples were profiled to compare A20-associated transcriptional patterns with cell-line data. Targeted DNA sequencing was performed in 11 ccRCC and 8 papillary RCC samples, and whole-exome sequencing was conducted in A20-overexpressing 786-O cells. Key genes were further evaluated using Kaplan-Meier survival analysis in 530 ccRCC patients and TCGA-KIRC data comprising 533 primary tumors and 72 normal samples. Results: GEO analysis showed significant TNFAIP3\/A20 upregulation in ccRCC (p = 3.96 \u00d7 10\u22125) and enrichment of NF-\u03baB-related gene sets (p = 0.01). A20 overexpression produced distinct phenotypes in HEK293 and 786-O cells. In HEK293 cells, A20 increased BIK and ARHGAP6 expression and was associated with increased apoptosis and reduced wound closure. In 786-O cells, A20 suppressed ARHGAP6 and APAF1 and was associated with increased proliferation, enhanced wound closure, and reduced apoptosis relative to EV controls. A20-high ccRCC samples showed enrichment of NF-\u03baB, TGF-\u03b2, DNA repair, mTOR\/metabolic, hypoxia, and proteasome-related pathways. Genomic analyses identified alterations in NF-\u03baB-related genes, including CARD10 and IRAK1. Conclusions: A20\/TNFAIP3 may exert cell-context-dependent effects in RCC and is associated with tumor-relevant transcriptional and genomic alterations requiring further validation.<\/jats:p>","DOI":"10.3390\/cancers18111775","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:06:56Z","timestamp":1780049216000},"page":"1775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Analysis of Genomic and Phenomic Data Reveals Context-Dependent Function of A20 (TNFAIP3) in Renal Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Nour Abu","family":"Jayab","sequence":"first","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2068-1089","authenticated-orcid":false,"given":"Burcu","family":"Yener","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Cancer Research, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2893-2872","authenticated-orcid":false,"given":"Reem Sami","family":"Alhamidi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-5349","authenticated-orcid":false,"given":"Mansi","family":"Bhavsar","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-0899","authenticated-orcid":false,"given":"Alaa Muayad","family":"Altaie","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3815-5879","authenticated-orcid":false,"given":"Muna Abdalla","family":"Alhammadi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidya Bijosh","family":"Mohan","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa Khamis","family":"Almazrouei","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Sahnoon","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rola","family":"Abujabal","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Institute for Nutritional Medicine, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-1938","authenticated-orcid":false,"given":"Basel","family":"Al-Ramadi","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-4590","authenticated-orcid":false,"given":"Riyad","family":"Bendardaf","sequence":"additional","affiliation":[{"name":"Center of Excellence for Cancer Research, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Oncology Unit, University Hospital Sharjah, Sharjah P.O. Box 72772, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5259-327X","authenticated-orcid":false,"given":"Iman M.","family":"Talaat","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Pathology Department, Faculty of Medicine, Alexandria University, Alexandria 21131, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-0868","authenticated-orcid":false,"given":"Rifat","family":"Hamoudi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Pathology Department, Faculty of Medicine, Alexandria University, Alexandria 21131, Egypt"},{"name":"BIMAI-Lab, Biomedically Informed Artificial Intelligence Laboratory, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Division of Surgery and Interventional Science, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/cmi.2011.59","article-title":"Regulation of NF-\u03baB signaling by the A20 deubiquitinase","volume":"9","author":"Shembade","year":"2012","journal-title":"Cell. Mol. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.jare.2024.07.030","article-title":"The molecular mechanism of NF-\u03baB dysregulation across different subtypes of renal cell carcinoma","volume":"72","author":"Jayab","year":"2025","journal-title":"J. Adv. 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