{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:21:21Z","timestamp":1791490881196,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Siirt University BAP Project","award":["2020-SI\u00dcTIP-009"],"award-info":[{"award-number":["2020-SI\u00dcTIP-009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. Methods: Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 \u03bcM) and OLE (75 \u03bcM) significantly increased miR-155-5p expression by 2.89-fold and 1.74-fold, respectively (p &lt; 0.05). Bioinformatics analyses have indicated that miR-155-5p interacts with critical oncogenic pathways such as KRAS, CDK2, NF-\u03baB, and TGF-\u03b2\/Smad2. Computational analyses have revealed that miR-155-5p interacts with 16 critical oncogenic targets, including KRAS and CDK2. Molecular docking studies showed that NAR binds to the Switch I\/II region of KRAS with a binding energy of \u22128.2 kcal\/mol, while OLE binds to the ATP-binding pocket of CDK2 with an affinity of \u22129.1 kcal\/mol. Pharmacokinetic evaluations revealed that NAR indicated high oral bioavailability (93.763% HIA) and full compliance with Lipinski\u2019s rules, while OLE required advanced formulation strategies due to its high polarity. Network pharmacology analyses have shown that NAR affects lysosomal functions and enzyme regulation, while OLE affects G protein-coupled receptors and oxidoreductase activity. Results: Results indicate that NAR and OLE exhibit antitumor effects through multiple mechanisms by increasing miR-155-5p expression and inhibiting critical oncogenic targets in prostate cancer. Conclusions: Findings suggest that the dietary intake of these natural compounds (citrus and olive products) should be considered in prostate cancer prevention strategies, shedding light on the epigenetic mechanisms of polyphenols in cancer treatment and contributing to the development of new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/genes17010079","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T16:03:16Z","timestamp":1767974596000},"page":"79","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating the Therapeutic Effects of Naringenin and Oleuropein on Prostate Cancer Cell Mat-LyLu via miR-155-5p: A Bioinformatics and Molecular Docking Analysis of KRAS and CDK2 Networks"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-5356","authenticated-orcid":false,"given":"Cigdem","family":"Gungormez","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Siirt University, 56100 Siirt, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hussain, Y., Mirzaei, S., Ashrafizadeh, M., Zarrabi, A., Hushmandi, K., and Khan, H. (2021). Quercetin and its nano-scale delivery systems in prostate cancer therapy: Paving the way for cancer elimination and reversing chemoresistance. Cancers, 13.","DOI":"10.3390\/cancers13071602"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhu, S., Hu, X., and Fan, Y. (2022). Association of triglyceride levels and prostate cancer: A Mendelian randomization study. BMC Urol., 22.","DOI":"10.1186\/s12894-022-01120-6"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9575","DOI":"10.7314\/APJCP.2014.15.22.9575","article-title":"Epidemiology, etiology, diagnosis and treatment of prostate cancer","volume":"15","author":"Daniyal","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wang, Y., He, J., Zhao, Q., Bo, J., Zhou, Y., Sun, H., Wang, J., and Liu, Z. (2024). Evaluating the predictive value of angiogenesis-related genes for prognosis and immunotherapy response in prostate adenocarcinoma using machine learning and experimental approaches. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1416914"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/biof.2083","article-title":"Identification and validation of the TRHDE-AS1\/hsa-miR-449a\/ADAMTS5 axis as a novel prognostic biomarker in prostate cancer","volume":"50","author":"Lian","year":"2024","journal-title":"Biofactors"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Majewska, Z., Zajkowska, M., P\u0105czek, S., Nowi\u0144ski, A.R., Sok\u00f3lska, W., Gryko, M., and Orywal, K. (2025). The Clinical Relevance of Tumor Biomarkers in Prostate Cancer\u2014A Review. Cancers, 17.","DOI":"10.3390\/cancers17233742"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1242\/dev.002006","article-title":"The regulation of genes and genomes by small RNAs","volume":"134","author":"Ambros","year":"2007","journal-title":"Development"},{"key":"ref_8","first-page":"D789","article-title":"BB cancer: An expression atlas of blood-based biomarkers in the early diagnosis of cancers","volume":"48","author":"Zuo","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e3016","DOI":"10.1002\/jgm.3016","article-title":"MicroRNA-guided gene expression in prostate cancer: Literature and database overview","volume":"20","author":"Bryzgunova","year":"2018","journal-title":"J. Gene Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10555-017-9724-7","article-title":"miR-155 in cancer drug resistance and as target for miRNA-based therapeutics","volume":"7","author":"Bayraktar","year":"2018","journal-title":"Cancer Metastasis Rev."},{"key":"ref_11","first-page":"2709","article-title":"The tumor suppressor role of miR-155-5p in gastric cancer","volume":"16","author":"Li","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e12936","DOI":"10.1002\/kjm2.12936","article-title":"FEZH2-mediated downregulation of miR-155-5p contributes to prostate cancer cell malignancy through SMAD2 and TAB2","volume":"41","author":"Bai","year":"2025","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"533","DOI":"10.3892\/mmr.2014.2744","article-title":"microRNA-155 promotes the proliferation of prostate cancer cells by targeting annexin 7","volume":"11","author":"Cai","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Su, M.C., Lee, A.M., Zhang, W., Maeser, D., Gruener, R.F., and Deng, Y. (2024). Computational modeling to identify drugs targeting metastatic castration-resistant prostate cancer characterized by heightened glycolysis. Pharmaceuticals, 17.","DOI":"10.3390\/ph17050569"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"317S","DOI":"10.1093\/ajcn\/81.1.317S","article-title":"Polyphenols and disease risk in epidemiologic studies","volume":"81","author":"Arts","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12937-016-0217-2","article-title":"An overview on the role of dietary phenolics for the treatment of cancers","volume":"15","author":"Anantharaju","year":"2016","journal-title":"Nutr. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00345-011-0822-9","article-title":"Chemoprevention of prostate cancer: An updated view","volume":"30","author":"Klein","year":"2012","journal-title":"World J. Urol."},{"key":"ref_18","first-page":"91","article-title":"Chemoprevention of prostate cancer with nutrients and supplements","volume":"3","author":"Tombal","year":"2011","journal-title":"Cancer Manag. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.lfs.2007.06.011","article-title":"Tea polyphenols for health promotion","volume":"81","author":"Khan","year":"2007","journal-title":"Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113956","DOI":"10.1016\/j.biopha.2022.113956","article-title":"Curcumin: An epigenetic regulator and its application in cancer","volume":"156","author":"Ming","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Salehi, B., Valere, P., Fokou, T., Sharifi-Rad, M., Zucca, P., Pezzani, R., Martins, N., and Sharifi-Rad, J. (2019). The Therapeutic Potential of Naringenin: A Review of Clinical Trials. Pharmaceuticals, 12.","DOI":"10.3390\/ph12010011"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/ejlt.201100096","article-title":"Hydrophilic antioxidants of virgin olive oil. Part 2: Biosynthesis and biotransformation of phenolic compounds in virgin olive oil as affected by agronomic and processing factors","volume":"113","author":"Rallo","year":"2011","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cannataro, R., Fazio, A., La Torre, C., Caroleo, M.C., and Cione, E. (2021). Polyphenols in the Mediterranean Diet: From Dietary Sources to microRNA Modulation. Antioxidants, 10.","DOI":"10.3390\/antiox10020328"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1007\/s00726-010-0788-8","article-title":"Synergic effect of \u03b1-tocopherol and naringenin in transglutaminase-induced differentiation of human prostate cancer cells","volume":"41","author":"Torricelli","year":"2011","journal-title":"Amino Acids"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9403","DOI":"10.1039\/D0RA10168K","article-title":"Ligand-based pharmacophore modeling, virtual screening and biological evaluation to identify novel TGR5 agonists","volume":"11","author":"Zhao","year":"2021","journal-title":"RSC Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.cub.2009.03.059","article-title":"Redefining microRNA targets","volume":"19","author":"Seitz","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Riffo-Campos, \u00c1.L., Riquelme, I., and Brebi-Mieville, P. (2016). Tools for sequence-based miRNA target prediction: What to choose?. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17121987"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.biopha.2018.07.008","article-title":"Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels","volume":"106","author":"Akgun","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1080\/01635581.2020.1807575","article-title":"Oleuropein: A Potential Inhibitor for Prostate Cancer Cell Motility by Blocking Voltage-Gated Sodium Channels","volume":"73","author":"Aktas","year":"2020","journal-title":"Nutr. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"220070","DOI":"10.1098\/rsob.220070","article-title":"miR-155-3p: Processing by-product or rising star in immunity and cancer?","volume":"12","author":"Dawson","year":"2022","journal-title":"Open Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zanoaga, O., Braicu, C., Chiroi, P., Andreea, N., Hajjar, N.A., and M\u0103rg\u0103rit, S. (2021). The Role of miR-155 in Nutrition: Modulating Cancer-Associated Inflammation. Nutrients, 13.","DOI":"10.3390\/nu13072245"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1111\/cas.12548","article-title":"Inhibition of transforming growth factor beta\/SMAD signal by MiR-155 is involved in arsenic trioxide-induced anti-angiogenesis in prostate cancer","volume":"105","author":"Ji","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/bbb\/zbaa089","article-title":"Selenium nanoparticles inhibit tumor metastasis in prostate cancer through upregulated miR-155-5p-related pathway","volume":"85","author":"Liao","year":"2021","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_34","first-page":"2444","article-title":"MicroRNA-155-5p suppresses the migration and invasion of lung adenocarcinoma A549 cells by targeting smad2","volume":"16","author":"Lin","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3892\/ol.2020.12215","article-title":"MicroRNA-155-5p inhibits the invasion and migration of prostate cancer cells by targeting SPOCK1","volume":"20","author":"Yao","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Rajendran, P., Abdelsalam, S.A., Renu, K., Veeraraghavan, V., Ben Ammar, R., and Ahmed, E.A. (2022). Polyphenols as Potent Epigenetics Agents for Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911712"},{"key":"ref_37","first-page":"505","article-title":"Oleuropein as An Effective Suppressor of Inflammation and MicroRNA-146a Expression in Patients with Rheumatoid Arthritis","volume":"25","author":"Mahi","year":"2023","journal-title":"Cell J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"204062231986480","DOI":"10.1177\/2040622319864805","article-title":"Dietary compounds as potential modulators of microRNA expression in psoriasis","volume":"10","author":"Kocic","year":"2019","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Filippi, A., Deculescu-Ioni\u021b\u0103, T., Hudi\u021b\u0103, A., Baldasici, O., G\u0103l\u0103\u021beanu, B., and Mocanu, M.M. (2025). Molecular Mechanisms of Dietary Compounds in Cancer Stem Cells from Solid Tumors: Insights into Colorectal, Breast, and Prostate Cancer. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020631"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/bab.2521","article-title":"The impact of oleuropein on miRNAs regulating cell death signaling pathway in human cervical cancer cells","volume":"71","author":"Shaygan","year":"2024","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_41","first-page":"1300","article-title":"MicroRNA-126-3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K\/PDK1\/AKT pathway","volume":"43","author":"Ichikawa","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1038\/onc.2016.409","article-title":"A CDK2 activity signature predicts outcome in CDK2-low cancers","volume":"36","author":"McCurdy","year":"2017","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.taap.2013.04.030","article-title":"CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth","volume":"272","author":"Lee","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/(SICI)1097-0045(199601)28:1<44::AID-PROS6>3.0.CO;2-O","article-title":"Point mutations in the Ki-ras2 gene of codon 12 in the Dunning R-3327 prostatic adenocarcinoma system","volume":"28","author":"Blount","year":"1996","journal-title":"Prostate"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s11010-010-0700-6","article-title":"miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS","volume":"350","author":"Xu","year":"2011","journal-title":"Mol. Cell. Biochem."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/1\/79\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T16:27:18Z","timestamp":1769444838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/1\/79"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,9]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["genes17010079"],"URL":"https:\/\/doi.org\/10.3390\/genes17010079","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,9]]}}}