{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:12:07Z","timestamp":1783134727203,"version":"3.54.6"},"reference-count":31,"publisher":"IMR Press","issue":"10","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81902399"],"award-info":[{"award-number":["81902399"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: It has been reported that ubiquitin specific peptidase 4 (USP4) was functional in several tumors, but its function and mechanism in gastric cancer were still unknown. Methods: Bioinformatic tools were used to predict the prognosis of gastric cancer patients and the expression levels of USP4 in gastric cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were carried out to detect the messenger RNA (mRNA) and protein levels. Cell viability of gastric cancer was evaluated by Cell Counting Kit-8 (CCK-8) assay. Cell line-derived xenograft models were established to evaluate the tumor growth of gastric cancer. Luciferase assay and immunoblotting were used to determine the activation of nuclear factor kappa B (NF-\u03baB) signaling. Results: The public database Kaplan-Meier Plotter showed that gastric cancer patients with high USP4 expression had a shorter overall survival or post-progression survival than the patients with decreased USP4. Further studies indicated that USP4 was elevated in gastric cancer tumor tissues. In contrast, knockdown of USP4 markedly inhibited gastric cancer cell growth, and suppressed the tumor growth of gastric cancer. Further studies revealed that USP4 knockdown significantly suppressed NF-\u03baB-driven luciferase activity, and inhibited the phosphorylation of NF-\u03baB p65 in gastric cancer cells. Additionally, qRT-PCR analysis showed that USP4 knockdown significantly downregulated the expressions of cyclin D2 (CCND2) and B cell leukemia\/lymphoma 2 (BCL2). We also found that USP4 knockdown decreased the expressions of phosphatase of regenerating liver-3 (PRL-3), in contrast, overexpression of PRL-3 attenuated the inhibitory effects of USP4 knockdown on NF-\u03baB signaling and cell viability in gastric cancer cells. Finally, PR-619, which has been proven to inhibit the activities of USP4 and other deubiquitinases, could inhibit cell viability and NF-\u03baB signaling in gastric cancer cells. Conclusions: This study indicated that elevated USP4 predicted a poor index for gastric cancer patients, and mediated gastric cancer cell growth by regulating PRL-3\/NF-\u03baB signaling, which suggested USP4 may be a novel therapeutic target for gastric cancer.<\/jats:p>","DOI":"10.31083\/j.fbl2710286","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:52:10Z","timestamp":1666227130000},"source":"Crossref","is-referenced-by-count":15,"title":["The Deubiquitinating Enzyme USP4 Functions as an Oncoprotein in Gastric Cancer and Mediates NF-\u03baB Signaling by Regulating PRL-3 Expression"],"prefix":"10.31083","volume":"27","author":[{"given":"Yuanyuan","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Nursing Management, The First Affiliated Hospital of Soochow University, 215006 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendao","family":"You","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 215006 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"You W, Zhang X, Ji M, Yu Y, Chen C, Xiong Y, et al. MiR-152-5p as a microRNA passenger strand special functions in human gastric cancer cells. International Journal of Biological Sciences. 2018; 14: 644\u2013653.","DOI":"10.7150\/ijbs.25272"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"You W, Xu L, Zhang X, Zou H, Shi D, Zhang H, et al. High-Throughput Screening Identifies miR-451 as a Pleiotropic Modulator That Suppresses Gastric Cancer Metastasis. SLAS Technology. 2017; 22: 136\u2013143.","DOI":"10.1177\/2211068216675858"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Thrift AP, El-Serag HB. Burden of Gastric Cancer. Clinical Gastroenterology and Hepatology. 2020; 18: 534\u2013542.","DOI":"10.1016\/j.cgh.2019.07.045"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018; 68: 394\u2013424.","DOI":"10.3322\/caac.21492"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Johnston FM, Beckman M. Updates on Management of Gastric Cancer. Current Oncology Reports. 2019; 21: 67.","DOI":"10.1007\/s11912-019-0820-4"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Yang Y, Kitagaki J, Wang H, Hou DX, Perantoni AO. Targeting the ubiquitin-proteasome system for cancer therapy. Cancer Science. 2009; 100: 24\u201328.","DOI":"10.1111\/j.1349-7006.2008.01013.x"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Zhang J, Wu H, Yi B, Zhou J, Wei L, Chen Y, et al. RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP-1. FEBS Letters. 2018; 592: 3092\u20133100.","DOI":"10.1002\/1873-3468.13225"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Harrigan JA, Jacq X, Martin NM, Jackson SP. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nature Reviews. Drug Discovery. 2018; 17: 57\u201378.","DOI":"10.1038\/nrd.2017.152"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Sokolova O, Naumann M. NF-kappaB Signaling in Gastric Cancer. Toxins (Basel). 2017; 9: 119.","DOI":"10.3390\/toxins9040119"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Gu J, Li X, Zhao L, Yang Y, Xue C, Gao Y, et al. The role of PKM2 nuclear translocation in the constant activation of the NF-\u03baB signaling pathway in cancer-associated fibroblasts.Cell Death Disease. 2021; 12: 291.","DOI":"10.1038\/s41419-021-03579-x"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Chen D, Liu Q, Cao G. ERCC6L promotes cell growth and metastasis in gastric cancer through activating NF-\u03baB signaling. Aging (Albany NY). 2021; 13: 20218\u201320228.","DOI":"10.18632\/aging.203387"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Zhang C, Tian W, Meng L, Qu L, Shou C. PRL-3 promotes gastric cancer migration and invasion through a NF-kappaB-HIF-1alpha-miR-210 axis. Journal of Molecular Medicine (Berlin, Germany). 2016; 94: 401\u2013415.","DOI":"10.1007\/s00109-015-1350-7"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Xing C, Lu XX, Guo PD, Shen T, Zhang S, He XS, et al. Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis. Cancer Research. 2016; 76: 83\u201395.","DOI":"10.1158\/0008-5472.CAN-14-3595"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Maksoud S. The Role of the Ubiquitin Proteasome System in Glioma: Analysis Emphasizing the Main Molecular Players and Therapeutic Strategies Identified in Glioblastoma Multiforme. Molecular Neurobiology. 2021; 58: 3252\u20133269.","DOI":"10.1007\/s12035-021-02339-4"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Geng N, Li Y, Zhang W, Wang F, Wang X, Jin Z, et al. A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis. International Journal of Cancer. 2020; 146: 1139\u20131151.","DOI":"10.1002\/ijc.32523"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Li F, Hu Q, He T, Xu J, Yi Y, Xie S, et al. The Deubiquitinase USP4 Stabilizes Twist1 Protein to Promote Lung Cancer Cell Stemness. Cancers (Basel). 2020; 12: 1582.","DOI":"10.3390\/cancers12061582"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Guo W, Ma J, Pei T, Zhao T, Guo S, Yi X, et al. Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma. Journal of Cellular and Molecular Medicine. 2018; 22: 2944\u20132954.","DOI":"10.1111\/jcmm.13603"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Sz\u00e1sz AM, L\u00e1nczky A, Nagy \u00c1, F\u00f6rster S, Hark K, Green JE, et al. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 2016; 7: 49322\u201349333.","DOI":"10.18632\/oncotarget.10337"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia. 2017; 19: 649\u2013658.","DOI":"10.1016\/j.neo.2017.05.002"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022; 25: 18\u201327.","DOI":"10.1016\/j.neo.2022.01.001"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Xu X, Wang J, Han K, Li S, Xu F, Yang Y. Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells. Cancer Science. 2018; 109: 1220\u20131229.","DOI":"10.1111\/cas.13540"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Ni D, Xu P, Gallagher S. Immunoblotting and Immunodetection. Current Protocols in Cell Biology. 2017; 74: 6.2.1\u20136.2.37.","DOI":"10.1002\/cpcb.18"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Kutner RH, Zhang XY, Reiser J. Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nature Protocols. 2009; 4: 495\u2013505.","DOI":"10.1038\/nprot.2009.22"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Altun M, Kramer HB, Willems LI, McDermott JL, Leach CA, Goldenberg SJ, et al. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chemistry & Biology. 2011; 18: 1401\u20131412.","DOI":"10.1016\/j.chembiol.2011.08.018"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Wang L, Li M, Sha B, Hu X, Sun Y, Zhu M, et al. Inhibition of deubiquitination by PR-619 induces apoptosis and autophagy via ubi-protein aggregation-activated ER stress in oesophageal squamous cell carcinoma. Cell Proliferation. 2021; 54: e12919.","DOI":"10.1111\/cpr.12919"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Zhou Y, Liang P, Ji W, Yu Z, Chen H, Jiang L. Ubiquitin-specific protease 4 promotes glioblastoma multiforme via activating ERK pathway. OncoTargets and Therapy. 2019; 12: 1825\u20131839.","DOI":"10.2147\/OTT.S176582"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Qin N, Han F, Li L, Ge Y, Lin W, Wang J, et al. Deubiquitinating enzyme 4 facilitates chemoresistance in glioblastoma by inhibiting P53 activity. Oncol Letter. 2019; 17: 958\u2013964.","DOI":"10.3892\/ol.2018.9654"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Nguyen HH, Kim T, Nguyen T, Hahn MJ, Yun SI, Kim KK. A Selective Inhibitor of Ubiquitin-Specific Protease 4 Suppresses Colorectal Cancer Progression by Regulating beta-Catenin Signaling. Cellular Physiology and Biochemistry. 2019; 53: 157\u2013171.","DOI":"10.33594\/000000127"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Chaithongyot S, Jantaree P, Sokolova O, Naumann M. NF-kappaB in Gastric Cancer Development and Therapy. Biomedicines. 2021; 9: 870.","DOI":"10.3390\/biomedicines9080870"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Xiao N, Li H, Luo J, Wang R, Chen H, Chen J, et al. Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha-induced cancer cell migration. The Biochemical Journal. 2012; 441: 979\u2013986.","DOI":"10.1042\/BJ20111358"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Fan YH, Yu Y, Mao RF, Tan XJ, Xu GF, Zhang H, et al. USP4 targets TAK1 to downregulate TNFalpha-induced NF-kappaB activation. Cell Death and Differentiation. 2011; 18: 1547\u20131560.","DOI":"10.1038\/cdd.2011.11"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/27\/10\/10.31083\/j.fbl2710286","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:18:19Z","timestamp":1732709899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/27\/10\/10.31083\/j.fbl2710286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":31,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022]]}},"alternative-id":["S2768-6701(22)00640-2"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2710286","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]},"article-number":"286"}}