USP7 promotes hepatoblastoma progression through activation of PI3K/AKT signaling pathway

Article type: Research Article

Authors: Ye, Mujie^{a; b; 1} | He, Jiajun^{a; b; 1} | Zhang, Jingjing^{c; 1} | Liu, Baihui^{a; b} | Liu, Xiangqi^{a; b} | Xie, Lulu^{a; b} | Wei, Meng^{a; b} | Dong, Rui^{a; b} | Li, Kai^{a; b} | Ma, Duan^{d; e; *} | Dong, Kuiran^{a; b; *}

Affiliations: [a] Department of Pediatric Surgery, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China | [b] Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China | [c] Department of Medical Imaging, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China | [d] 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 | [e] Shanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai, China

Correspondence: [*] Corresponding authors: Duan Ma, 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, 200032, China. E-mail: duanma@fudan.edu.cn. Kuiran Dong, Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai, 201102, China. E-mail: kuirand@hotmail.com.

Note: [1] These authors contributed equally to this work as first author.

Abstract: 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.

Keywords: Hepatoblastoma, signaling pathway, inhibitor, apoptosis, proliferation, metastasis

DOI: 10.3233/CBM-200052

Journal: Cancer Biomarkers, vol. 31, no. 2, pp. 107-117, 2021