{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:09:07Z","timestamp":1786964947465,"version":"build-2736575974"},"reference-count":41,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012046","name":"Vietnam Academy of Science and Technology","doi-asserted-by":"crossref","award":["NCXS.01.03\/23-25"],"award-info":[{"award-number":["NCXS.01.03\/23-25"]}],"id":[{"id":"10.13039\/100012046","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Prostate cancer (PCa) is one of the most common malignant tumors of the male urinary system, and its incidence and mortality rates have been increasing worldwide. Benign prostatic hyperplasia (BPH) represents stromal and epithelial cell proliferation in the prostate in elderly males. Abnormal activation of inflammation-related signalling molecules, such as toll-like receptor 4 (TLR4) and Janus kinase\/signal transducers and activators of transcription (JAK\/STAT) has been linked to the initiation and progression of various human diseases including PCa and BPH. Cylindromatosis (CYLD) gene alterations are associated with PCa progression. In this study, the contribution of CYLD, JAK2, and TLR4 gene variants to PCa and BPH risks and their associations with prostate-specific antigen (PSA) levels, immunophenotype, and clinical features in Vietnamese men were determined. Methods: A total of 102 patients with PCa, 65 with BPH, and 114 healthy controls were enrolled. The immunophenotype was analyzed by flow cytometry, cytokine secretion by enzyme-linked immunosorbent assay (ELISA), and gene variants by DNA sequencing. Results: Lower levels of transforming growth factor \u03b2 (TGF-\u03b2) and higher numbers of CD13+CD117- and CD56+CD25+ cells were observed in the PCa group than in the BPH group. Genetic analysis of the CYLD gene identified five single nucleotide polymorphisms (SNPs), of which c.2351-47 C&gt;T, c.2351-46A&gt;T, and rs1971432171 T&gt;G had significantly higher frequencies in PCa patients than in the control and BPH groups. Sequencing of the TLR4 gene revealed five nucleotide changes, in which the rs2149356 SNP showed an increased risk for both PCa and BPH and the c.331-206 SNP had a reduced risk for PCa. Importantly, the expansion of activated natural killer (NK) cells and higher levels of PSA were found in PCa patients carrying the CT genotype of the CYLD c.2351-47 compared to those with the wild-type genotype. Conclusion: Activation of NK cells in CYLD-sensitive PCa patients was associated with serum PSA release and the CYLD c.2351-47 variant may be a significant risk factor for prostatitis in PCa patients.<\/jats:p>","DOI":"10.31083\/j.fbl2907256","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T08:46:33Z","timestamp":1721378793000},"source":"Crossref","is-referenced-by-count":5,"title":["Associations of CYLD, JAK2 and TLR4 Genotypes with PSA Levels and Immunophenotype in Benign Prostatic Hyperplasia and Prostate Cancer"],"prefix":"10.31083","volume":"29","author":[{"given":"Le Vu","family":"Duy","sequence":"first","affiliation":[{"name":"Oncology Center, 103 Military Hospital, Vietnam Military Medical University, Ha Dong, 151530 Hanoi, Vietnam"},{"name":"Radiology Center, 103 Military Hospital, Vietnam Military Medical University, Ha Dong, 151530 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pham Thi","family":"Huong","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Trung","family":"Nam","sequence":"first","affiliation":[{"name":"Institute of Biotechnology, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Thi","family":"Trang","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghiem Thi Minh","family":"Chau","sequence":"first","affiliation":[{"name":"Oncology Center, 103 Military Hospital, Vietnam Military Medical University, Ha Dong, 151530 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Thi Phuong","family":"Thao","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Huy","family":"Hoang","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thien","family":"Tao","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can Van","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, Vietnam Military Medical University, Ha Dong, 151530 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3494-5136","authenticated-orcid":true,"given":"Nguyen Thi","family":"Xuan","sequence":"first","affiliation":[{"name":"Institute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, 122300 Hanoi, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209\u2013249.","DOI":"10.3322\/caac.21660"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Zhu X, Albertsen PC, Andriole GL, Roobol MJ, Schr\u00f6der FH, Vickers AJ. Risk-based prostate cancer screening. European Urology. 2012; 61: 652\u2013661.","DOI":"10.1016\/j.eururo.2011.11.029"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA: A Cancer Journal for Clinicians. 2017; 67: 7\u201330.","DOI":"10.3322\/caac.21387"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"De Nunzio C, Presicce F, Tubaro A. Inflammatory mediators in the development and progression of benign prostatic hyperplasia. Nature Reviews. Urology. 2016; 13: 613\u2013626.","DOI":"10.1038\/nrurol.2016.168"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gr\u00f6nberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nature Reviews. Cancer. 2007; 7: 256\u2013269.","DOI":"10.1038\/nrc2090"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Cao D, Sun R, Peng L, Li J, Huang Y, Chen Z, et al. Immune Cell Proinflammatory Microenvironment and Androgen-Related Metabolic Regulation During Benign Prostatic Hyperplasia in Aging. Frontiers in Immunology. 2022; 13: 842008.","DOI":"10.3389\/fimmu.2022.842008"},{"key":"ref7","unstructured":"Guo X, Sun X, Ye P. The Diagnostic Value of Serum TGF-\u03b21, p2PSA Combined with PSA in Prostate Cancer. Alternative Therapies in Health and Medicine. 2023. (online ahead of print)"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Rozkov\u00e1 D, Tiserov\u00e1 H, Fuc\u00edkov\u00e1 J, Last\u2019ovicka J, Podrazil M, Ulcov\u00e1 H, et al. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clinical Immunology (Orlando, Fla.). 2009; 131: 1\u201310.","DOI":"10.1016\/j.clim.2009.01.001"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Lerman I, Garcia-Hernandez MDLL, Rangel-Moreno J, Chiriboga L, Pan C, Nastiuk KL, et al. Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase. Molecular Cancer Research: MCR. 2017; 15: 1138\u20131152.","DOI":"10.1158\/1541-7786.MCR-17-0003"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"H\u00f6fner T, Klein C, Eisen C, Rigo-Watermeier T, Haferkamp A, Trumpp A, et al. The influence of prostatic anatomy and neurotrophins on basal prostate epithelial progenitor cells. The Prostate. 2016; 76: 114\u2013121.","DOI":"10.1002\/pros.23109"},{"key":"ref11","unstructured":"Curnis F, Arrigoni G, Sacchi A, Fischetti L, Arap W, Pasqualini R, et al. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Research. 2002; 62: 867\u2013874."},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Harris KS, Shi L, Foster BM, Mobley ME, Elliott PL, Song CJ, et al. CD117\/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance. Scientific Reports. 2021; 11: 1465.","DOI":"10.1038\/s41598-021-81126-6"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Ghosh M, Subramani J, Rahman MM, Shapiro LH. CD13 restricts TLR4 endocytic signal transduction in inflammation. Journal of Immunology (Baltimore, Md.: 1950). 2015; 194: 4466\u20134476.","DOI":"10.4049\/jimmunol.1403133"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Wang W, Wang J. Toll-Like Receptor 4 (TLR4)\/Cyclooxygenase-2 (COX-2) Regulates Prostate Cancer Cell Proliferation, Migration, and Invasion by NF-\u03baB Activation. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2018; 24: 5588\u20135597.","DOI":"10.12659\/MSM.906857"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Stars\u00edchov\u00e1 A, Lincov\u00e1 E, Pernicov\u00e1 Z, Kozub\u00edk A, Soucek K. TGF-beta1 suppresses IL-6-induced STAT3 activation through regulation of Jak2 expression in prostate epithelial cells. Cellular Signalling. 2010; 22: 1734\u20131744.","DOI":"10.1016\/j.cellsig.2010.06.014"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Kim HJ, Bae JS, Chang IH, Kim KD, Lee J, Shin HD, et al. Sequence variants of Toll-like receptor 4 (TLR4) and the risk of prostate cancer in Korean men. World Journal of Urology. 2012; 30: 225\u2013232.","DOI":"10.1007\/s00345-011-0690-3"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Qureshi ST, Larivi\u00e8re L, Leveque G, Clermont S, Moore KJ, Gros P, et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). The Journal of Experimental Medicine. 1999; 189: 615\u2013625.","DOI":"10.1084\/jem.189.4.615"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Hellmig S, Fischbach W, Goebeler-Kolve ME, F\u00f6lsch UR, Hampe J, Schreiber S. Association study of a functional Toll-like receptor 4 polymorphism with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. Leukemia & Lymphoma. 2005; 46: 869\u2013872.","DOI":"10.1080\/1042819050086451"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Kwon EM, Holt SK, Fu R, Kolb S, Williams G, Stanford JL, et al. Androgen metabolism and JAK\/STAT pathway genes and prostate cancer risk. Cancer Epidemiology. 2012; 36: 347\u2013353.","DOI":"10.1016\/j.canep.2012.04.002"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Haq S, Sarodaya N, Karapurkar JK, Suresh B, Jo JK, Singh V, et al. CYLD destabilizes NoxO1 protein by promoting ubiquitination and regulates prostate cancer progression. Cancer Letters. 2022; 525: 146\u2013157.","DOI":"10.1016\/j.canlet.2021.10.032"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Gu Y, Wu S, Fan J, Meng Z, Gao G, Liu T, et al. CYLD regulates cell ferroptosis through Hippo\/YAP signaling in prostate cancer progression. Cell Death & Disease. 2024; 15: 79.","DOI":"10.1038\/s41419-024-06464-5"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Yang WL, Jin G, Li CF, Jeong YS, Moten A, Xu D, et al. Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling. Science Signaling. 2013; 6: ra3.","DOI":"10.1126\/scisignal.2003197"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Jenner MW, Leone PE, Walker BA, Ross FM, Johnson DC, Gonzalez D, et al. Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood. 2007; 110: 3291\u20133300.","DOI":"10.1182\/blood-2007-02-075069"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Song LH, Toan NL, Xuan NT, Uhlemann AC, Boldt ABW, Duy DN, et al. A promoter polymorphism in the interferon alpha-2 gene is associated with the clinical presentation of hepatitis B. Mutation Research. 2006; 601: 137\u2013143.","DOI":"10.1016\/j.mrfmmm.2006.06.011"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Huyen NT, Ngoc NT, Giang NH, Trang DT, Hanh HH, Binh VD, et al. CYLD stimulates macrophage phagocytosis of leukemic cells through STAT1 signalling in acute myeloid leukemia. PLoS ONE. 2023; 18: e0283586.","DOI":"10.1371\/journal.pone.0283586"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Wurm R, Just S, Wang X, Wex K, Schmid U, Blanchard N, et al. Protective dendritic cell responses against listeriosis induced by the short form of the deubiquitinating enzyme CYLD are inhibited by full-length CYLD. European Journal of Immunology. 2015; 45: 1366\u20131376.","DOI":"10.1002\/eji.201445116"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Cleynen I, Vazeille E, Artieda M, Verspaget HW, Szczypiorska M, Bringer MA, et al. Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. Gut. 2014; 63: 1265\u20131274.","DOI":"10.1136\/gutjnl-2012-303205"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Trang DT, Giang NH, Trang BK, Ngoc NT, Giang NV, Canh NX, et al. Prevalence of CYLD mutations in Vietnamese patients with polycythemia vera. Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University. 2022; 31: 369\u2013380.","DOI":"10.17219\/acem\/144027"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Falchook AD, Martin NE, Basak R, Smith AB, Milowsky MI, Chen RC. Stage at presentation and survival outcomes of patients with Gleason 8-10 prostate cancer and low prostate-specific antigen. Urologic Oncology. 2016; 34: 119.e19\u2013e26.","DOI":"10.1016\/j.urolonc.2015.09.014"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Li Y, Huang W, Xu Y, Zhou L, Liang Y, Gao C, et al. CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-\u03baB Inflammatory Signaling in Mesangial Cells. BioMed Research International. 2017; 2017: 3982906.","DOI":"10.1155\/2017\/3982906"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science (New York, N.Y.). 2011; 331: 44\u201349.","DOI":"10.1126\/science.1198687"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Zhang Z, Zhang S, Jiang X, Wu D, Du Y, Yang XD. Spata2L Suppresses TLR4 Signaling by Promoting CYLD-Mediated Deubiquitination of TRAF6 and TAK1. Biochemistry. Biokhimiia. 2022; 87: 957\u2013964.","DOI":"10.1134\/S0006297922090085"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S. Association of TLR2 and TLR4 polymorphisms with risk of cancer: a meta-analysis. PLoS ONE. 2013; 8: e82858.","DOI":"10.1371\/journal.pone.0082858"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Zheng SL, Augustsson-B\u00e4lter K, Chang B, Hedelin M, Li L, Adami HO, et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Research. 2004; 64: 2918\u20132922.","DOI":"10.1158\/0008-5472.CAN-03-3280"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Cheng I, Plummer SJ, Casey G, Witte JS. Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2007; 16: 352\u2013355.","DOI":"10.1158\/1055-9965.EPI-06-0429"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"Luo Y, Yang X, Basourakos SP, Zuo X, Wei D, Zhao J, et al. Enzalutamide-Resistant Progression of Castration-Resistant Prostate Cancer Is Driven via the JAK2\/STAT1-Dependent Pathway. Frontiers in Molecular Biosciences. 2021; 8: 652443.","DOI":"10.3389\/fmolb.2021.652443"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"Sfanos KS, Hempel HA, De Marzo AM. The role of inflammation in prostate cancer. Advances in Experimental Medicine and Biology. 2014; 816: 153\u2013181.","DOI":"10.1007\/978-3-0348-0837-8_7"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"Gallazzi M, Baci D, Mortara L, Bosi A, Buono G, Naselli A, et al. Prostate Cancer Peripheral Blood NK Cells Show Enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 Production and Secrete Monocyte-Recruiting and Polarizing Factors. Frontiers in Immunology. 2021; 11: 586126.","DOI":"10.3389\/fimmu.2020.586126"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Li M, Xu DM, Lin SB, Yang ZL, Xu TY, Yang JH, et al. Investigation of Lymphocyte Subsets in Peripheral Blood of Patients with Benign Prostatic Hyperplasia. International Journal of General Medicine. 2021; 14: 6951\u20136959.","DOI":"10.2147\/IJGM.S340018"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Chen Z, Tong L, Neo SY, Li S, Gao J, Schlisio S, et al. CD25bright NK cells display superior function and metabolic activity under regulatory T cell-mediated suppression. Oncoimmunology. 2023; 12: 2175517.","DOI":"10.1080\/2162402X.2023.2175517"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Nagao T, Kurosu T, Umezawa Y, Nogami A, Oshikawa G, Tohda S, et al. Proliferation and survival signaling from both Jak2-V617F and Lyn involving GSK3 and mTOR\/p70S6K\/4EBP1 in PVTL-1 cell line newly established from acute myeloid leukemia transformed from polycythemia vera. PLoS ONE. 2014; 9: e84746.","DOI":"10.1371\/journal.pone.0084746"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/29\/7\/10.31083\/j.fbl2907256","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T14:39:22Z","timestamp":1732718362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/29\/7\/10.31083\/j.fbl2907256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":41,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024]]}},"alternative-id":["S2768-6701(24)01393-5"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2907256","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]},"article-number":"256"}}