{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T02:07:07Z","timestamp":1779934027134,"version":"3.53.1"},"reference-count":76,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011851","name":"Kom op tegen Kanker","doi-asserted-by":"publisher","award":["Startersbeurs"],"award-info":[{"award-number":["Startersbeurs"]}],"id":[{"id":"10.13039\/501100011851","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014382","name":"Ipsen","doi-asserted-by":"publisher","award":["Unrestricted research grant"],"award-info":[{"award-number":["Unrestricted research grant"]}],"id":[{"id":"10.13039\/501100014382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["Unrestricted research grant"],"award-info":[{"award-number":["Unrestricted research grant"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fonds voor wetenschappelijk onderzoek Vlaanderen","award":["Aspirant fundamenteel onderzoek"],"award-info":[{"award-number":["Aspirant fundamenteel onderzoek"]}]},{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","award":["Unrestricted research grant"],"award-info":[{"award-number":["Unrestricted research grant"]}],"id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Economy, Industry and Competitiveness MEIC\/AEI","award":["RTI2018-095039-B-I00"],"award-info":[{"award-number":["RTI2018-095039-B-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2\u03b1 and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel\u2013Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2\u03b1 are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2\u03b1, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2\u03b1, VEGFR1 and\/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and\/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2\u03b1 expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2\u03b1 inhibitor belzutifan.<\/jats:p>","DOI":"10.3390\/cancers13123099","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T22:40:37Z","timestamp":1624315237000},"page":"3099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["MicroRNAs Targeting HIF-2\u03b1, VEGFR1 and\/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2\u03b1 Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7479-4793","authenticated-orcid":false,"given":"Lisa","family":"Kinget","sequence":"first","affiliation":[{"name":"Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-5536","authenticated-orcid":false,"given":"Eduard","family":"Roussel","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-863X","authenticated-orcid":false,"given":"Annelies","family":"Verbiest","sequence":"additional","affiliation":[{"name":"Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"Albersen","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rodr\u00edguez-Antona","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osvaldo","family":"Gra\u00f1a-Castro","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Inglada-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Statistics and Operational Research, Faculty of Medicine, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Zucman-Rossi","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, Universit\u00e9 de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, \u00e9quipe Labellis\u00e9e Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Couchy","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, Universit\u00e9 de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, \u00e9quipe Labellis\u00e9e Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Job","sequence":"additional","affiliation":[{"name":"Programme Cartes d\u2019Identit\u00e9 des Tumeurs, Ligue Nationale Contre le Cancer, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"de Reyni\u00e8s","sequence":"additional","affiliation":[{"name":"Programme Cartes d\u2019Identit\u00e9 des Tumeurs, Ligue Nationale Contre le Cancer, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annouschka","family":"Laenen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0882-2944","authenticated-orcid":false,"given":"Marcella","family":"Baldewijns","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Beuselinck","sequence":"additional","affiliation":[{"name":"Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. 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