{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:43:42Z","timestamp":1764679422608,"version":"3.46.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2018\/31\/B\/NZ5\/02238"],"award-info":[{"award-number":["2018\/31\/B\/NZ5\/02238"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>SOX (SRY-related HMG-box) transcription factors are key regulators of embryogenesis and vascular development, with emerging roles in cancer biology. In non-small-cell lung cancer (NSCLC), the contributions of SOX18 and SOX30 remain insufficiently understood, particularly regarding their epigenetic regulation and network interactions with angiogenic and immune-modulatory pathways. We examined 800 NSCLC specimens (400 lung adenocarcinomas, 400 squamous cell carcinomas) using immunohistochemistry, RT-qPCR, Western blotting, and spatial transcriptomics to profile SOX18, SOX30, and related signaling partners (SOX7, SOX17, MEF2C\u2014Myocyte Enhancer Factor 2C, VCAM1\u2014Vascular Cell Adhesion Molecule 1, p-STAT3\u2014Signal Transducer and Activator of Transcription 3). Epigenetic regulation was assessed via droplet digital methylation-specific PCR of promoter CpG islands, while functional validation employed adenoviral delivery of hsa-miR-24-3p in NSCLC cell lines and 3D spheroid cultures. SOX18 protein was markedly overexpressed in both NSCLC subtypes, despite reduced transcript levels and consistent promoter hypermethylation, suggesting post-transcriptional regulation. In contrast, SOX30 expression was uniformly downregulated at both mRNA and protein levels, frequently linked to promoter hypermethylation, especially in squamous carcinoma. Spatial transcriptomics revealed SOX18 enrichment at tumor cores and invasive borders, co-localizing with MEF2C, VCAM1, and p-STAT3 in vascular and stromal niches, while SOX30 expression remained low across all tumor regions. Functional assays demonstrated that hsa-miR-24-3p suppressed SOX18 expression and partially modulated SOX30 and MEF2C, reinforcing a miRNA-driven regulatory axis. In summary, SOX18 and SOX30 play divergent roles in NSCLC progression: SOX18 functions as a pro-oncogenic factor driving angiogenesis and tumor\u2013stroma interactions, while SOX30 acts as an epigenetically silenced tumor suppressor. Regulation of SOX18 by miR-24-3p highlights a potential therapeutic vulnerability. These findings underscore the significance of SOX transcription factors as biomarkers and potential targets for novel treatment strategies in NSCLC.<\/jats:p>","DOI":"10.3390\/ijms262311669","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:39:43Z","timestamp":1764679183000},"page":"11669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SOX18 and SOX30 in NSCLC: The Epigenetic Landscape of Methylation, miRNA Regulation, and Network Crosstalk in Tumor Progression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1972-1524","authenticated-orcid":false,"given":"Mateusz","family":"Olbromski","sequence":"first","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4093-7386","authenticated-orcid":false,"given":"Aleksandra","family":"Piotrowska","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Mrozowska","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicja","family":"Kmiecik","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6901-1240","authenticated-orcid":false,"given":"Natalia","family":"Glatzel-Plucinska","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-1055","authenticated-orcid":false,"given":"Agnieszka","family":"Gomulkiewicz","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Stepien","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2668-3873","authenticated-orcid":false,"given":"Klaudia","family":"Krawczynska","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5694-0638","authenticated-orcid":false,"given":"Piotr","family":"Blasiak","sequence":"additional","affiliation":[{"name":"Department and Clinic of Thoracic Surgery, Wroclaw Medical University, Grabiszynska 105, 53-439 Wroclaw, Poland"},{"name":"Lower Silesian Center of Oncology, Pulmonology and Hematology, Hirszfelda 12, 53-413 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzenna","family":"Podhorska-Okolow","sequence":"additional","affiliation":[{"name":"Division of Ultrastructural Research, Wroclaw Medical University, 50-368 Wroclaw, Poland"},{"name":"Department of Human Biology, Faculty of Physiotherapy, Wroclaw University of Health and Sport Sciences, 51-612 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Dziegiel","sequence":"additional","affiliation":[{"name":"Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"},{"name":"Department of Human Biology, Faculty of Physiotherapy, Wroclaw University of Health and Sport Sciences, 51-612 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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