{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:48:22Z","timestamp":1762235302574,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"crossref","award":["110-2320-B-A49A-515","110-2314-B-002-113","111-2314-B-002-240-MY3","111-2320-B-039-021-MY3","111-2218-E-037-001","112-2218-E-037-001","113-2218-E-037-001","112-2314-B-037-127","113-2314-B-037-016","114-2320-B-039-024-MY3"],"award-info":[{"award-number":["110-2320-B-A49A-515","110-2314-B-002-113","111-2314-B-002-240-MY3","111-2320-B-039-021-MY3","111-2218-E-037-001","112-2218-E-037-001","113-2218-E-037-001","112-2314-B-037-127","113-2314-B-037-016","114-2320-B-039-024-MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000272","name":"National Health Research Institute","doi-asserted-by":"crossref","award":["NHRI-EX113-11313SI"],"award-info":[{"award-number":["NHRI-EX113-11313SI"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004694","name":"Kaohsiung Medical University","doi-asserted-by":"crossref","award":["KMUH110-0R54","KMUH111-IR58","KMUH112-2R59","KMUH113-3R52"],"award-info":[{"award-number":["KMUH110-0R54","KMUH111-IR58","KMUH112-2R59","KMUH113-3R52"]}],"id":[{"id":"10.13039\/501100004694","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"crossref","award":["CMU111-MF-09","CMU112-MF-10","CMU113-TC-04","CMU113-MF-11"],"award-info":[{"award-number":["CMU111-MF-09","CMU112-MF-10","CMU113-TC-04","CMU113-MF-11"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objective: Biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer indicates disease progression. Although type 2 diabetes mellitus (T2D) shows a paradoxical association with prostate cancer risk, the prognostic role of T2D-related genetic variants remains unclear. Methods: We analyzed 113 common T2D susceptibility-related single-nucleotide polymorphisms (SNPs) in 644 Taiwanese men with localized prostate cancer (D\u2019Amico risk classification: 12% low, 34% intermediate, and 54% high) treated with RP. Associations between SNPs and BCR were assessed using Cox regression, adjusting for key clinicopathological factors. Functional annotation was performed using HaploReg and FIVEx, while The Cancer Genome Atlas transcriptomic data were analyzed for C2 calcium-dependent domain-containing 4A (C2CD4A) expression. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore related biological pathways. Results:\u00a0C2CD4A SNP rs4502156 was independently associated with a reduced risk of BCR (hazard ratio = 0.80, p = 0.035). The protective C allele correlated with higher C2CD4A expression. Low C2CD4A expression is associated with advanced pathological stages, higher Gleason scores, and disease progression. GSEA revealed negative enrichment of mitotic and chromatid segregation pathways in high-C2CD4A-expressing tumors, with E2F targets being the most suppressed. GSVA confirmed an inverse correlation between C2CD4A expression and E2F pathway activity, with CDKN2C as a co-expressed functional gene. Conclusions: The T2D-related variant rs4502156 in C2CD4A independently predicts a lower risk of BCR, potentially via suppression of the E2F pathway, and may serve as a germline biomarker for postoperative risk stratification.<\/jats:p>","DOI":"10.3390\/diagnostics15212767","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:55:22Z","timestamp":1762178122000},"page":"2767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interplay Between Type 2 Diabetes Susceptibility and Prostate Cancer Progression: Functional Insights into C2CD4A"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-5172","authenticated-orcid":false,"given":"Yei-Tsung","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Fen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, China Medical University, Taichung 406, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lih-Chyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Yuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Cheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 907, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor Chia-Hsiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan"},{"name":"School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-6004","authenticated-orcid":false,"given":"Te-Ling","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, China Medical University, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Pin","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Institute of Medical Science and Technology, College of Medicine, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5510-6513","authenticated-orcid":false,"given":"Bo-Ying","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, China Medical University, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"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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