MDM2-P53 Signaling Pathway-Mediated Upregulation of CDC20 Promotes Progression of Human Diffuse Large B-Cell Lymphoma

Chengtao Sun,1,* Mengzhen Li,1,* Yanfen Feng,2,3,* Feifei Sun,2,4 Li Zhang,2,4 Yanjie Xu,1 Suying Lu,2,4 Jia Zhu,2,4 Junting Huang,2,4 Juan Wang,2,4 Yang Hu,1 Yizhuo Zhang1,2,4 1Department of Hematology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 2Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People’s Republic of China; 3Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yizhuo Zhang Tel/ Fax +86-20-87343799Email yizhuozhang111@163.comBackground: Cell-division cycle 20 (CDC20) is overexpressed in a variety of tumor cells and is negatively regulated by wild-type p53 (wtp53). Our previous study uncovered that CDC20 was upregulated and associated with poor outcome in diffuse large B-cell lymphoma (DLBCL) based on bioinformatics analysis. Dysregulation of the MDM2-p53 is a major mechanism to promote DLBCL. Thus, we hypothesized that CDC20 could be a downstream gene of the MDM2-p53 signaling pathway. However, the clinical significance and mechanistic role of a novel MDM2-p53-CDC20 signaling pathway in DLBCL have still remained unclear.Materials and Methods: RT-qPCR was performed in MDM2 knocked down (KD) and control (Ctrl) OCI-Ly3/OCI-Ly10 cells to investigate whether CDC20 was a downstream gene of the MDM2-p53 pathway. The effects of CDC20 on cell proliferation, cell cycle and apoptosis were assessed, as well as the role of CDC20 in suppressing tumorigenicity in vivo. Furthermore, we also investigated the roles of CDC20 and MDM2 in progression of DLBCL and the underlying mechanisms.Results: The results of RT-qPCR revealed that CDC20 was downregulated while TP53 was upregulated in MDM2 KD OCI-Ly3 and OCI-Ly10 cells. It was unveiled that the expression levels of CDC20 and MDM2 were upregulated in DLBCL tissues and cells, and high CDC20 expression was correlated with adverse clinical features and poor outcome. Functional assays showed that downregulation of CDC20 could inhibit proliferation, induce apoptosis and cell cycle arrest in vitro. In addition, inactivation of the MDM2-p53 pathway by downregulation of MDM2 restored wtp53 expression level and reduced CDC20 protein level in OCI-Ly3 and OCI-Ly10 cells. Besides, targeting CDC20 was found to suppress tumorigenesis of DLBCL in vivo.Conclusion: CDC20 was identified as a key downstream gene of the MDM2-p53 signaling pathway in DLBCL and may be used as a novel target gene to guide therapeutic applications.Keywords: DLBCL, MDM2-p53 signaling pathway, CDC20, tumor progression