{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:06:24Z","timestamp":1790856384422,"version":"4.1.0"},"reference-count":21,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Next Generation EU\u2014Italian Ministry of University and Research PNRR \u201cNational Center for Gene Therapy and Drugs based on RNA Technology\u201d","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"Italian Ministry of University and Research","award":["PRIN PNRR P2022C9HJY"],"award-info":[{"award-number":["PRIN PNRR P2022C9HJY"]}]},{"name":"CNR projects","award":["FOE-2021 DBA.AD005.225"],"award-info":[{"award-number":["FOE-2021 DBA.AD005.225"]}]},{"name":"CNR projects","award":["FOE-2022 DSB.AD006.371.001"],"award-info":[{"award-number":["FOE-2022 DSB.AD006.371.001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prolyl 3-hydroxylase 2 (P3H2) is a key enzyme involved in the architecture of the extracellular matrix (ECM). While previously shown to be regulated by VEGF-A and to play a role in angiogenesis, its function in cancer remains ambiguous. While characterized as a tumor suppressor, its precise function in colorectal cancer (CRC) progression is poorly defined. Bioinformatic analysis and patient data reveal that P3H2 transcript levels are significantly reduced in colon adenocarcinoma tissues, showing a progressive decline in metastatic lesions. Furthermore, VEGF-A exposure upregulates P3H2 transcripts in the HCT116 CRC cell line. To investigate its impact in CRC, we generated a stable HCT116 clone overexpressing P3H2. In vitro studies demonstrated that while P3H2 overexpression inhibited anchorage-independent growth, it significantly enhanced cellular invasion without altering cell proliferation. In vivo, however, P3H2-overexpressing tumors exhibited accelerated tumor growth and a statistically significant increase in lung metastases. P3H2 overexpression remodeled the tumor microenvironment (TME) by modifying its main substrate, Collagen IV, resulting in the induction of increased vessels density. Our study repositions P3H2 as a dynamic enzymatic switch within the TME. This work identifies P3H2-driven ECM remodeling as a promising therapeutic axis in advanced CRC, with particular relevance for combination strategies targeting angiogenesis.<\/jats:p>","DOI":"10.3390\/ijms27041999","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:57:29Z","timestamp":1771516649000},"page":"1999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prolyl 3-Hydroxylase 2 Supports a Pro-Angiogenic Milieu Promoting Colorectal Cancer Progression and Metastasis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8290-6521","authenticated-orcid":false,"given":"Sonia","family":"Panico","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Adinolfi","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9400-3279","authenticated-orcid":false,"given":"Sara Magliacane","family":"Trotta","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"D\u2019Orsi","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"},{"name":"BIOVIIIX s.r.l., Department of R&D, 80128 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Mercadante","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-3859","authenticated-orcid":false,"given":"Andrea","family":"Paradisi","sequence":"additional","affiliation":[{"name":"Apoptosis, Cancer and Development Laboratory\u2014Equipe labellis\u00e9e \u2018La Ligue\u2019, LabEx DEVweCAN, Centre de Recherche en Canc\u00e9rologie de Lyon, INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Mehlen","sequence":"additional","affiliation":[{"name":"Apoptosis, Cancer and Development Laboratory\u2014Equipe labellis\u00e9e \u2018La Ligue\u2019, LabEx DEVweCAN, Centre de Recherche en Canc\u00e9rologie de Lyon, INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-4402","authenticated-orcid":false,"given":"Valeria","family":"Tarallo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-1697","authenticated-orcid":false,"given":"Sandro","family":"De Falco","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"},{"name":"BIOVIIIX s.r.l., Department of R&D, 80128 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.bbrc.2004.03.060","article-title":"LEPREL1, a novel ER and Golgi resident member of the Leprecan family","volume":"317","author":"Kjellman","year":"2004","journal-title":"Biochem. 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