{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T17:41:09Z","timestamp":1776966069847,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010609","name":"GUMed \u201cGranty na granty\u201d","doi-asserted-by":"publisher","award":["71-01422\/K16-0007254"],"award-info":[{"award-number":["71-01422\/K16-0007254"]}],"id":[{"id":"10.13039\/501100010609","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clear-cell renal cell carcinoma (ccRCC) is characterised by constitutive activation of hypoxia-inducible factors (HIFs) following VHL loss, which contributes to tumour progression and therapeutic resistance. Given the limitations of VEGFR-targeted therapies, we investigated the biological and potential therapeutic relevance of the HIF axis in ccRCC. Nuclear and cytoplasmic HIF1A and EPAS1\/HIF2A expression were assessed by immunohistochemistry in tumours from 40 patients and correlated with clinicopathological parameters and cancer-specific survival. The functional effects of HIF pathway inhibitors (GN44028, KC7F2, and FM19G11) and sunitinib were analysed in VHL-mutant 786-O and VHL-wild-type Caki-1 cell lines using SRB viability assay, cell cycle analysis, wound closure assay, and RT-qPCR of HIF-related genes, with comparison to non-malignant HK-2 cells. TCGA-ccRCC data from advanced-stage patients (III\u2013IV, n = 185) were analysed as a complementary transcriptomic context. Nuclear, but not cytoplasmic, HIF1A and EPAS1\/HIF2A expression was associated with advanced stage and shorter survival in univariable analyses. GN44028 showed the most pronounced antiproliferative effect under tested conditions and was associated with broad suppression of HIF-related transcription, whereas sunitinib was associated with increased expression of selected HIF-related genes. GN44028 did not demonstrate clear selectivity over non-malignant HK-2 cells. Overall, nuclear HIF activation is associated with aggressive ccRCC biology, and broader HIF pathway modulation warrants further experimental investigation; however, the clinical findings remain exploratory, and therapeutic selectivity and translational relevance are not yet established.<\/jats:p>","DOI":"10.3390\/ijms27083505","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T14:24:58Z","timestamp":1776176698000},"page":"3505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploratory Multi-Level Analysis of the HIF Axis in Clear-Cell Renal Cell Carcinoma and Evaluation of GN44028 as an Experimental HIF Pathway-Modulating Compound"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4310-1616","authenticated-orcid":false,"given":"Piotr M.","family":"Wierzbicki","sequence":"first","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Rybarczyk","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-5417","authenticated-orcid":false,"given":"Mateusz","family":"Czajkowski","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacek","family":"Kie\u017cun","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-709 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3537-4710","authenticated-orcid":false,"given":"Bart\u0142omiej E.","family":"Krazi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-709 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Olszewska","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8621-5755","authenticated-orcid":false,"given":"Marzena","family":"Kogut-Wierzbicka","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Academy of Applied Medical and Sciences, 82-300 Elbl\u0105g, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzanna","family":"Ruda\u015b","sequence":"additional","affiliation":[{"name":"Student Scientific Circle, Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Kierczak","sequence":"additional","affiliation":[{"name":"Student Scientific Circle, Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0205-4698","authenticated-orcid":false,"given":"Karol","family":"Mitas","sequence":"additional","affiliation":[{"name":"Student Scientific Circle, Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3044-6244","authenticated-orcid":false,"given":"Laura","family":"Wro\u0144ska","sequence":"additional","affiliation":[{"name":"Student Scientific Circle, Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0687-3089","authenticated-orcid":false,"given":"Michalina","family":"Grudzi\u0144ska","sequence":"additional","affiliation":[{"name":"Student Scientific Circle, Department of Urology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8390-6980","authenticated-orcid":false,"given":"Patrik da Silva","family":"Vital","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Pio XII Foundation, Barretos Cancer Hospital, Barretos 14780-360, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Kotulak-Chrz\u0105szcz","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Medical University of Gda\u0144sk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.eururo.2022.03.006","article-title":"European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update","volume":"82","author":"Ljungberg","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.semcancer.2012.06.001","article-title":"The VHL\/HIF Axis in Clear Cell Renal Carcinoma","volume":"23","author":"Shen","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1158\/2159-8290.CD-18-1354","article-title":"The Metabolic Basis of Kidney Cancer","volume":"9","author":"Linehan","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ccell.2015.12.004","article-title":"An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma","volume":"29","author":"Hakimi","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrc1187","article-title":"Targeting HIF-1 for Cancer Therapy","volume":"3","author":"Semenza","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1200\/JCO.23.02082","article-title":"Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09)","volume":"42","author":"Tannir","year":"2024","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal Cell Carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3892\/ijmm.2022.5114","article-title":"Expression Levels of Sonic Hedgehog Pathway Genes and Their Targets Are Upregulated in Early Clear Cell Renal Cell Carcinoma","volume":"49","author":"Rybarczyk","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0140-6736(24)00917-6","article-title":"Renal Cell Carcinoma","volume":"404","author":"Young","year":"2024","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.annonc.2024.05.537","article-title":"Renal Cell Carcinoma: ESMO Clinical Practice Guideline for Diagnosis, Treatment and Follow-Up","volume":"35","author":"Powles","year":"2024","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1038\/s41591-020-1093-z","article-title":"Targeting the HIF2\u2013VEGF Axis in Renal Cell Carcinoma","volume":"26","author":"Choueiri","year":"2020","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1056\/NEJMoa2103425","article-title":"Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease","volume":"385","author":"Jonasch","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Song, G., Xue, S., Zhu, Y., Wu, C., and Ji, X. (2024). The Efficacy and Safety of Belzutifan Inhibitor in Patients with Advanced or Metastatic Clear Cell Renal Cell Carcinoma: A Meta-Analysis. BMC Pharmacol. Toxicol., 25.","DOI":"10.1186\/s40360-024-00828-5"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kotulak-Chrzaszcz, A., Kiezun, J., Czajkowski, M., Matuszewski, M., Klacz, J., Krazinski, B.E., Godlewski, J., Kmiec, Z., and Wierzbicki, P.M. (2023). The Immunoreactivity of GLI1 and VEGFA Is a Potential Prognostic Factor in Kidney Renal Clear Cell Carcinoma. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11622-7"},{"key":"ref_16","first-page":"371","article-title":"Prognostic Significance of VHL, HIF1A, HIF2A, VEGFA and P53 Expression in Patients with Clear-cell Renal Cell Carcinoma Treated with Sunitinib as First-line Treatment","volume":"55","author":"Wierzbicki","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1093\/annonc\/mdz056","article-title":"Renal Cell Carcinoma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up","volume":"30","author":"Escudier","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.eururo.2016.02.029","article-title":"The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs\u2014Part A: Renal, Penile, and Testicular Tumours","volume":"70","author":"Moch","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6545","DOI":"10.1007\/s00330-022-08738-y","article-title":"[68Ga]Ga-PSMA-11 PET\/CT Has Potential Application in Predicting Tumor HIF-2\u03b1 Expression and Therapeutic Response to HIF-2\u03b1 Antagonists in Patients with RCC","volume":"32","author":"Meng","year":"2022","journal-title":"Eur. Radiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e9407","DOI":"10.48101\/ujms.v129.9407","article-title":"Expression of HIF-\u03b1 and Their Association with Clinicopathological Parameters in Clinical Renal Cell Carcinoma","volume":"129","author":"Sitaram","year":"2024","journal-title":"Ups. J. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cao, D., Hou, M., Guan, Y., Jiang, M., Yang, Y., and Gou, H. (2009). Expression of HIF-1alpha and VEGF in Colorectal Cancer: Association with Clinical Outcomes and Prognostic Implications. BMC Cancer, 9.","DOI":"10.1186\/1471-2407-9-432"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.hoc.2023.04.011","article-title":"Von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology","volume":"37","author":"Shirole","year":"2023","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1038\/s41467-021-23448-7","article-title":"A Small Molecule HIF-1\u03b1 Stabilizer That Accelerates Diabetic Wound Healing","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41467-021-27801-8","article-title":"Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers","volume":"13","author":"Theocharidis","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34052","DOI":"10.18632\/oncotarget.8570","article-title":"HIF-1-Alpha Links Mitochondrial Perturbation to the Dynamic Acquisition of Breast Cancer Tumorigenicity","volume":"7","author":"Kuo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.molcel.2014.04.026","article-title":"O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway","volume":"54","author":"Ferrer","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/s41419-025-07752-4","article-title":"Oncometabolite Fumarate Facilitates PD-L1 Expression and Immune Evasion in Clear Cell Renal Cell Carcinoma","volume":"16","author":"Gao","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100929","DOI":"10.1016\/j.drup.2023.100929","article-title":"Sunitinib Resistance in Renal Cell Carcinoma: From Molecular Mechanisms to Predictive Biomarkers","volume":"67","author":"Jin","year":"2023","journal-title":"Drug Resist. Updates"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/ajco.12465","article-title":"Intrinsic Resistance to Sunitinib in Patients with Metastatic Renal Cell Carcinoma","volume":"13","author":"Lim","year":"2017","journal-title":"Asia Pac. J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1021\/ml3004632","article-title":"Discovery of Indenopyrazoles as a New Class of Hypoxia Inducible Factor (HIF)-1 Inhibitors","volume":"4","author":"Minegishi","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2490830","DOI":"10.1080\/07853890.2025.2490830","article-title":"Construction and Validation of Renal Cell Carcinoma Tumor Cell Differentiation-Related Prognostic Classification (RCC-TCDC): An Integrated Bioinformatic Analysis and Clinical Study","volume":"57","author":"Liu","year":"2025","journal-title":"Ann. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.21037\/tcr-22-2692","article-title":"Establishment and Validation of a Prognostic Nomogram for Patients with Renal Cell Carcinoma Based on SEER and TCGA Database","volume":"12","author":"Wang","year":"2023","journal-title":"Transl. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.2217\/fon-2023-0679","article-title":"Belzutifan: A Novel Therapeutic for the Management of von Hippel-Lindau Disease and Beyond","volume":"20","author":"Curry","year":"2024","journal-title":"Future Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Roviello, G., De Gennaro, I., Vascotto, I., Venturi, G., D\u2019Angelo, A., Winchler, C., Guarino, A., Cacioppo, S., Modesti, M., and Mela, M.M. (2024). Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies. Genes, 16.","DOI":"10.3390\/genes16010006"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1080\/15548627.2024.2421699","article-title":"Atractylenolide I Inhibits Angiogenesis and Reverses Sunitinib Resistance in Clear Cell Renal Cell Carcinoma through ATP6V0D2-Mediated Autophagic Degradation of EPAS1\/HIF2\u03b1","volume":"21","author":"Li","year":"2025","journal-title":"Autophagy"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41586-024-08507-5","article-title":"A Neoantigen Vaccine Generates Antitumour Immunity in Renal Cell Carcinoma","volume":"639","author":"Braun","year":"2025","journal-title":"Nature"},{"key":"ref_37","unstructured":"Tavassoli, F.A., and Devilee, P. (2006). Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, IARC Press. World Health Organization Classification of Tumours."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41585-019-0211-5","article-title":"The Cancer Genome Atlas of Renal Cell Carcinoma: Findings and Clinical Implications","volume":"16","author":"Linehan","year":"2019","journal-title":"Nat. Rev. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kiezun, J., Kiezun, M., Krazinski, B.E., Paukszto, L., Koprowicz-Wielguszewska, A., Kmiec, Z., and Godlewski, J. (2022). Galanin Receptors (GALR1, GALR2, and GALR3) Immunoexpression in Enteric Plexuses of Colorectal Cancer Patients: Correlation with the Clinico-Pathological Parameters. Biomolecules, 12.","DOI":"10.3390\/biom12121769"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.exer.2015.06.024","article-title":"Distribution of Galanin Receptors in the Human Eye","volume":"138","author":"Trost","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_41","first-page":"138","article-title":"Vorschlag Zur Einheitlichen Definition Eines Immunreaktiven Score (IRS) F\u00fcr Den Immunhistochemischen Ostrogenrezeptor-Nachweis (ER-ICA) Im Mammakarzinomgewebe [Recommendation for Uniform Definition of an Immunoreactive Score (IRS) for Immunohistochemical Estrogen Receptor Detection (ER-ICA) in Breast Cancer Tissue]","volume":"8","author":"Remmele","year":"1987","journal-title":"Pathologe"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6128","DOI":"10.1158\/1078-0432.CCR-08-3180","article-title":"Identification of a Novel Small Molecule HIF-1\u03b1 Translation Inhibitor","volume":"15","author":"Narita","year":"2009","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1111\/cas.16204","article-title":"Hexokinase 2 Nonmetabolic Function-Mediated Phosphorylation of I\u03baB\u03b1 Enhances Pancreatic Ductal Adenocarcinoma Progression","volume":"115","author":"Tong","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41389-021-00361-8","article-title":"Heterogeneity of Subsets in Glioblastoma Mediated by Smad3 Palmitoylation","volume":"10","author":"Fan","year":"2021","journal-title":"Oncogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1016\/j.bmcl.2015.04.088","article-title":"Ortho-Carboranylphenoxyacetanilides as Inhibitors of Hypoxia-Inducible Factor (HIF)-1 Transcriptional Activity and Heat Shock Protein (HSP) 60 Chaperon Activity","volume":"25","author":"Li","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1074\/jbc.M109.008326","article-title":"FM19G11, a New Hypoxia-Inducible Factor (HIF) Modulator, Affects Stem Cell Differentiation Status","volume":"285","author":"Erceg","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1001\/jama.295.21.2516","article-title":"Sunitinib in Patients with Metastatic Renal Cell Carcinoma","volume":"295","author":"Motzer","year":"2006","journal-title":"JAMA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/nprot.2006.179","article-title":"Sulforhodamine B Colorimetric Assay for Cytotoxicity Screening","volume":"1","author":"Vichai","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12473","DOI":"10.1007\/s13277-014-2566-9","article-title":"Identification of a Suitable qPCR Reference Gene in Metastatic Clear Cell Renal Cell Carcinoma","volume":"35","author":"Wierzbicki","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"109288","DOI":"10.1016\/j.steroids.2023.109288","article-title":"PDIA3 Modulates Genomic Response to 1,25-Dihydroxyvitamin D3 in Squamous Cell Carcinoma of the Skin","volume":"199","author":"Nowak","year":"2023","journal-title":"Steroids"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.parkreldis.2018.02.023","article-title":"Cerebrospinal Fluid Biomarkers of Central Dopamine Deficiency Predict Parkinson\u2019s Disease","volume":"50","author":"Goldstein","year":"2018","journal-title":"Park. Relat. Disord."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/hec.4495","article-title":"A Nonlinear Dynamic Factor Model of Health and Medical Treatment","volume":"31","author":"Peracchi","year":"2022","journal-title":"Health Econ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4709","DOI":"10.1002\/sim.5878","article-title":"Adjustment for Measurement Error in Evaluating Diagnostic Biomarkers by Using an Internal Reliability Sample","volume":"32","author":"White","year":"2013","journal-title":"Stat. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3892\/or.2017.5642","article-title":"Overexpression of the YAP1 Oncogene in Clear Cell Renal Cell Carcinoma Is Associated with Poor Outcome","volume":"38","author":"Rybarczyk","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v039.i05","article-title":"Regularization Paths for Cox\u2019s Proportional Hazards Model via Coordinate Descent","volume":"39","author":"Simon","year":"2011","journal-title":"J. Stat. Softw."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Vittinghoff, E., Glidden, D.V., Shiboski, S.C., and McCulloch, C.E. (2012). Regression Methods in Biostatistics: Linear, Logistic, Survival, and Repeated Measures Models, Springer. Statistics for Biology and Health.","DOI":"10.1007\/978-1-4614-1353-0"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T17:06:14Z","timestamp":1776963974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083505"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083505","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]}}}