{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:19:12Z","timestamp":1779297552352,"version":"3.51.4"},"reference-count":43,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CBM"],"published-print":{"date-parts":[[2021,6,18]]},"abstract":"<jats:p>BACKGROUND: Hepatoblastoma (HB) is an embryonic solid tumor and the most common primary malignant liver tumor in children. HB usually occurs in infants and children. Although treatment diversity is increasing, some patients still have very poor prognosis. Many studies have investigated USP7 inhibitors for tumors. Using database information, we found that USP7 is highly expressed in HB. METHODS: Lentivirus-mediated USP7 knockdown and overexpression was performed in HB cell lines HepG2 and Huh6. CCK8 and transwell assays were used to determine cell viability and metastasis. Flow cytometry was used to study cell cycle and apoptosis. Levels of proteins were detected using western blots. RESULTS: Downregulation of USP7 resulted in significant decrease in cell proliferation, clonal formation, and cell migration and invasion. With overexpression of USP7, cellular malignant behavior increased. Cell cycle assays showed that USP7 knockdown inhibited G1 to S phase transition in the cell cycle. Upregulation of USP7 promoted the transition. Animal experiments showed USP7 facilitated tumor growth in vivo. Western blots indicated that USP7 may affect HB tumorigenesis through the PI3K\/AKT signaling pathway. Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K\/AKT pathway. CONCLUSION: USP7 upregulation contributed to HB genesis and development through the PI3K\/AKT signaling pathway. USP7 could be a potential target for future HB treatment.<\/jats:p>","DOI":"10.3233\/cbm-200052","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:36:16Z","timestamp":1616765776000},"page":"107-117","source":"Crossref","is-referenced-by-count":24,"title":["USP7 promotes hepatoblastoma progression through activation of PI3K\/AKT signaling pathway"],"prefix":"10.1177","volume":"31","author":[{"given":"Mujie","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"},{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"},{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China"},{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baihui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lulu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duan","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, Collaborative Innovation Center of Genetics and Development, School of Basic Medical Sciences, Fudan University, Shanghai, China"},{"name":"Shanghai Key Lab of Birth Defect, Children\u2019s Hospital of Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuiran","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China"},{"name":"Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"key":"10.3233\/CBM-200052_ref1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.12688\/f1000research.12239.1","article-title":"Hepatoblastoma: current understanding, recent advances, and controversies","volume":"7","author":"Czauderna","year":"2018","journal-title":"F1000Res"},{"key":"10.3233\/CBM-200052_ref2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00247-018-4085-0","article-title":"Pediatric hepatoblastoma and hepatocellular carcinoma: lessons learned in the last decade","volume":"48","author":"Khanna","year":"2018","journal-title":"Pediatr Radiol"},{"key":"10.3233\/CBM-200052_ref3","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/ccr3.1515","article-title":"Hepatoblastoma in a child with dextrocardia and possible histopathological alteration reminiscent of hepatocellular carcinoma after neoadjuvant chemotherapy","volume":"6","author":"Papry","year":"2018","journal-title":"Clin Case Rep"},{"key":"10.3233\/CBM-200052_ref4","doi-asserted-by":"crossref","first-page":"900","DOI":"10.7150\/thno.29515","article-title":"CircHMGCS1 promotes hepatoblastoma cell proliferation by regulating the IGF signaling pathway and glutaminolysis","volume":"9","author":"Zhen","year":"2019","journal-title":"Theranostics"},{"key":"10.3233\/CBM-200052_ref5","doi-asserted-by":"crossref","unstructured":"I. Cristobal, M. Sanz-Alvarez, M. Luque, C. Carames, F. Rojo and J. Garcia-Foncillas, The role of MicroRNAs in hepatoblastoma tumors, Cancers (Basel) 11 (2019).","DOI":"10.3390\/cancers11030409"},{"key":"10.3233\/CBM-200052_ref6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.clon.2019.03.044","article-title":"Retrospective analysis of childhood hepatoblastoma in a single centre in China","volume":"31","author":"Wang","year":"2019","journal-title":"Clin Oncol (R Coll Radiol)"},{"key":"10.3233\/CBM-200052_ref7","doi-asserted-by":"crossref","unstructured":"I.I.P. Lim, A.J. Bondoc, J.I. Geller and G.M. Tiao, Hepatoblastoma-the evolution of biology, surgery, and transplantation, Children (Basel) 6 (2018).","DOI":"10.3390\/children6010001"},{"key":"10.3233\/CBM-200052_ref8","doi-asserted-by":"crossref","unstructured":"B.N. Ofoegbu, S.E.E. Abdel Salam, W.G. Diehl and L. Ghosn, Congenital hepatoblastoma in a growing health economy, BMJ Case Rep 12 (2019).","DOI":"10.1136\/bcr-2017-223344"},{"key":"10.3233\/CBM-200052_ref9","doi-asserted-by":"crossref","unstructured":"T. Yang, J. Yang, T. Tan, J. Pan, C. Hu, J. Li and Y. Zou, Cure of hepatoblastoma through transcatheter arterial chemoembolization, Glob Pediatr Health 4 (2017), 2333794X17742750.","DOI":"10.1177\/2333794X17742750"},{"key":"10.3233\/CBM-200052_ref10","doi-asserted-by":"crossref","unstructured":"P. Dall\u2019Igna, L. Brugieres, A.S. Christin, R. Maibach, M. Casanova, R. Alaggio, J.V. de Goyet, J. Zsiros, B. Morland, P. Czauderna, M. Childs, D.C. Aronson, S. Branchereau, P. Brock and G. Perilongo, Hepatoblastoma in children aged less than six months at diagnosis: a report from the SIOPEL group, Pediatr Blood Cancer 65 (2018).","DOI":"10.1002\/pbc.26791"},{"key":"10.3233\/CBM-200052_ref11","doi-asserted-by":"crossref","unstructured":"D. Oh, N.J. Yi, S. Song, O.K. Kim, S.K. Hong, K.C. Yoon, S.W. Ahn, H.S. Kim, H. Kim, H.Y. Kim, H.J. Kang, M. Lee, K.B. Lee, K.W. Lee and K.S. Suh, Split liver transplantation for retroperitoneal immature teratoma masquerading as hepatoblastoma, Pediatr Transplant 21 (2017).","DOI":"10.1111\/petr.13025"},{"key":"10.3233\/CBM-200052_ref12","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.theriogenology.2019.06.014","article-title":"Surface sperm cell ubiquitination directly impaired blastocyst formation rate after intracytoplasmic sperm injection in pig","volume":"135","author":"Petelak","year":"2019","journal-title":"Theriogenology"},{"key":"10.3233\/CBM-200052_ref13","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1038\/s41467-019-10374-y","article-title":"Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion","volume":"10","author":"Lee","year":"2019","journal-title":"Nat Commun"},{"key":"10.3233\/CBM-200052_ref14","doi-asserted-by":"crossref","unstructured":"D. Wang, F. Bu and W. Zhang, The role of ubiquitination in regulating embryonic stem cell maintenance and cancer development, Int J Mol Sci 20 (2019).","DOI":"10.3390\/ijms20112667"},{"key":"10.3233\/CBM-200052_ref15","doi-asserted-by":"crossref","unstructured":"X. Ma, Y. Dang, X. Shao, X. Chen, F. Wu and Y. Li, Ubiquitination and long non-coding RNAs regulate actin cytoskeleton regulators in cancer progression, Int J Mol Sci 20 (2019).","DOI":"10.3390\/ijms20122997"},{"key":"10.3233\/CBM-200052_ref16","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ydbio.2019.05.015","article-title":"Ubiquitination is required for the initial removal of paternal organelles in C. elegans","volume":"453","author":"Molina","year":"2019","journal-title":"Dev Biol"},{"key":"10.3233\/CBM-200052_ref17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fcell.2019.00043","article-title":"Ubiquitination as a key regulator of endosomal signaling by GPCRs","volume":"7","author":"Burton","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"10.3233\/CBM-200052_ref18","doi-asserted-by":"crossref","unstructured":"T. Xu, Y. Guo and X. Qi, Ubiquitination-mediated inflammasome activation during bacterial infection, Int J Mol Sci 20 (2019).","DOI":"10.3390\/ijms20092110"},{"key":"10.3233\/CBM-200052_ref19","doi-asserted-by":"crossref","first-page":"4817","DOI":"10.1038\/onc.2017.220","article-title":"DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer","volume":"36","author":"Hernandez-Perez","year":"2017","journal-title":"Oncogene"},{"key":"10.3233\/CBM-200052_ref20","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3389\/fgene.2019.00422","article-title":"EZH2 regulates protein stability via recruiting USP7 to mediate neuronal gene expression in cancer cells","volume":"10","author":"Lei","year":"2019","journal-title":"Front Genet"},{"key":"10.3233\/CBM-200052_ref21","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41467-019-08334-7","article-title":"Usp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie","volume":"10","author":"Sun","year":"2019","journal-title":"Nat Commun"},{"key":"10.3233\/CBM-200052_ref22","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3389\/fphar.2019.00427","article-title":"USP7: novel drug target in cancer therapy","volume":"10","author":"Wang","year":"2019","journal-title":"Front Pharmacol"},{"key":"10.3233\/CBM-200052_ref23","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1159\/000484062","article-title":"The USP7 inhibitor P5091 induces cell death in ovarian cancers with different P53 status","volume":"43","author":"Wang","year":"2017","journal-title":"Cell Physiol Biochem"},{"key":"10.3233\/CBM-200052_ref24","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1016\/j.celrep.2016.02.049","article-title":"USP7 enforces heterochromatinization of p53 target promoters by protecting SUV39H1 from MDM2-mediated degradation","volume":"14","author":"Mungamuri","year":"2016","journal-title":"Cell Rep"},{"key":"10.3233\/CBM-200052_ref25","doi-asserted-by":"crossref","first-page":"35508","DOI":"10.18632\/oncotarget.16348","article-title":"Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated\/deleted clones","volume":"8","author":"Carra","year":"2017","journal-title":"Oncotarget"},{"key":"10.3233\/CBM-200052_ref26","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/ncb1469","article-title":"FOXO4 transcriptional activity is regulated by monoubiquitination and USP7\/HAUSP","volume":"8","author":"van der Horst","year":"2006","journal-title":"Nat Cell Biol"},{"key":"10.3233\/CBM-200052_ref27","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature24451","article-title":"Molecular basis of USP7 inhibition by selective small-molecule inhibitors","volume":"550","author":"Turnbull","year":"2017","journal-title":"Nature"},{"key":"10.3233\/CBM-200052_ref28","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/nature24006","article-title":"USP7 small-molecule inhibitors interfere with ubiquitin binding","volume":"550","author":"Kategaya","year":"2017","journal-title":"Nature"},{"key":"10.3233\/CBM-200052_ref29","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.bbrc.2017.01.144","article-title":"Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway","volume":"484","author":"Zhan","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"10.3233\/CBM-200052_ref30","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/JLB.2A1017-420RR","article-title":"Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF-kappaB signaling pathway in multiple myeloma","volume":"104","author":"Yao","year":"2018","journal-title":"J Leukoc Biol"},{"key":"10.3233\/CBM-200052_ref31","doi-asserted-by":"crossref","first-page":"609","DOI":"10.2147\/OTT.S182806","article-title":"Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy","volume":"12","author":"Fu","year":"2019","journal-title":"Onco Targets Ther"},{"key":"10.3233\/CBM-200052_ref32","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.bbrc.2019.03.093","article-title":"The m6A demethylase FTO promotes the growth of lung cancer cells by regulating the m6A level of USP7 mRNA","volume":"512","author":"Li","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"10.3233\/CBM-200052_ref33","doi-asserted-by":"crossref","first-page":"31815","DOI":"10.18632\/oncotarget.16463","article-title":"The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells","volume":"8","author":"Morra","year":"2017","journal-title":"Oncotarget"},{"key":"10.3233\/CBM-200052_ref34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.dnarep.2019.02.005","article-title":"USP7: structure, substrate specificity, and inhibition","volume":"76","author":"Pozhidaeva","year":"2019","journal-title":"DNA Repair (Amst)"},{"key":"10.3233\/CBM-200052_ref35","doi-asserted-by":"crossref","first-page":"e867","DOI":"10.1038\/cddis.2013.400","article-title":"USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis","volume":"4","author":"Fan","year":"2013","journal-title":"Cell Death Dis"},{"key":"10.3233\/CBM-200052_ref36","first-page":"543","article-title":"Ubiquitinspecific protease 7 promotes osteosarcoma cell metastasis by inducing epithelialmesenchymal transition","volume":"41","author":"Zeng","year":"2019","journal-title":"Oncol Rep"},{"key":"10.3233\/CBM-200052_ref37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1620\/tjem.239.165","article-title":"Expression of USP7 and MARCH7 is correlated with poor prognosis in epithelial ovarian cancer","volume":"239","author":"Zhang","year":"2016","journal-title":"Tohoku J Exp Med"},{"key":"10.3233\/CBM-200052_ref38","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1007\/s13277-014-2773-4","article-title":"USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma","volume":"36","author":"Zhao","year":"2015","journal-title":"Tumour Biol"},{"key":"10.3233\/CBM-200052_ref39","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1158\/1078-0432.CCR-18-1740","article-title":"USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in t-cell leukemia","volume":"25","author":"Jin","year":"2019","journal-title":"Clin Cancer Res"},{"key":"10.3233\/CBM-200052_ref40","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.celrep.2017.09.072","article-title":"USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating beta-catenin deubiquitination","volume":"21","author":"Novellasdemunt","year":"2017","journal-title":"Cell Rep"},{"key":"10.3233\/CBM-200052_ref41","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41419-019-1943-0","article-title":"DPEP1 is a direct target of miR-193a-5p and promotes hepatoblastoma progression by PI3K\/Akt\/mTOR pathway","volume":"10","author":"Cui","year":"2019","journal-title":"Cell Death Dis"},{"key":"10.3233\/CBM-200052_ref42","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.freeradbiomed.2015.11.022","article-title":"Momordin Ic couples apoptosis with autophagy in human hepatoblastoma cancer cells by reactive oxygen species (ROS)-mediated PI3K\/Akt and MAPK signaling pathways","volume":"90","author":"Mi","year":"2016","journal-title":"Free Radic Biol Med"},{"key":"10.3233\/CBM-200052_ref43","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.omto.2020.09.008","article-title":"S119N mutation of the E3 ubiquitin ligase SPOP suppresses SLC7A1 degradation to regulate hepatoblastoma progression","volume":"19","author":"He","year":"2020","journal-title":"Mol Ther Oncolytics"}],"container-title":["Cancer Biomarkers"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/CBM-200052","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:08:09Z","timestamp":1777385289000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/CBM-200052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,18]]},"references-count":43,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.3233\/cbm-200052","relation":{},"ISSN":["1875-8592","1574-0153"],"issn-type":[{"value":"1875-8592","type":"electronic"},{"value":"1574-0153","type":"print"}],"subject":[],"published":{"date-parts":[[2021,6,18]]}}}