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Background: Although p53 mutation is uncommon in Epstein–Barr virus-linked gastric carcinoma, p53 suppression occurs through mechanisms like USP7 inhibition via EBV nuclear antigen-1 (EBNA1) activity. Therefore, this study evaluated the effect of EBNA1 on p53-inhibiting genes’ expression and the impact of USP7 inhibition on p53 suppression.
Materials and Methods:The MKN-45 cell was transfected with the EBNA1plasmid. According to hygromycin B resistance, a stable EBNA1 expression cell line was developed by selection. MDM4, MDM2, SIRT3, HDAC1, PSMD10, USP7, and p53 expression were checked using real-time PCR, and morphological changes were examined by pathological staining. Moreover, cells harboring EBNA1 or a control plasmid were treated with GNE-6776, and the expression of interest genes and viability of cells was evaluated.
Results: MDM4, MDM2, and PSMD10 were upregulated significantly(P<0.05) in the MKN-45 cell line following EBNA1 transfection. Morphological changes were observed in cells harboring EBNA1 after 20 days. In control cells, USP7 inhibition significantly (P<0.05) upregulated the HDAC1, PSMD10, MDM4, and MDM2 genes after 24h, but downregulated them after four days. In EBNA1harboring cells, MDM2, MDM4, and PSMD10 genes were upregulated significantly (P<0.05) after 24h, and this effect was sustained for all except MDM4 even after four days. Furthermore, USP7 inhibition induced apoptosis in both cell groups.
Conclusion: EBNA1 induces the expression of some p53-inhibiting genes. Following USP7 protein inhibition, two events, including p53 upregulation at the protein level and activation of apoptosis, suggested the idea of function and importance of EBNA1-USP7 interaction in the p53 suppression need more investigation, and it maybe needs reconsideration.

Type of Study: Full Length | Subject: Cancer Biology

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