The Oncogenic Role of APC/C Activator Protein Cdc20 by an Integrated Pan-Cancer Analysis in Human Tumors

Abstract

The landscape of CDC20 gene expression and its biological impacts across different types of cancers remains largely unknown. Here, a pan-cancer analysis was performed to analyze the role of Cdc20 in various human cancers. Our results indicated that the expression levels of the CDC20 gene were significantly elevated in bladder cancer, breast cancer, colon cancer, rectum cancer, stomach cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, prostate cancer, pancreatic cancer, and uterine cancer. In addition, the expression of CDC20 was significantly and positively correlated with the increase of clinical stages in multiple cancer types, including breast cancer, kidney cancer, and lung cancer, et al. Among 33 cancer subtypes in the TCGA dataset, the high expression of CDC20 was correlated with poor prognosis in 10 cancer types. Furthermore, the abundance of phosphorylated Cdc20 in the primary tumor was elevated and correlated with increased tumor grade. Next, we sought to elucidate the oncogenic role by analyzing its association with immune infiltration. For most cancer types, the CDC20 expression was positively correlated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells. To further understand its functional activity, we explored the classic Cdc20 downstream substrates, which were found to be mutually exclusive with the expression of Cdc20. Moreover, the pan-cancer analysis of the molecular function of Cdc20 indicated that BUB1, CCNA2, CCNB1, CDK1, MAD2L1, and PLK1 might play a critical role in interaction with Cdc20. The abundance of Cdc20 was further validated at transcriptional and translational levels with a publicly available dataset and clinical tumor tissues. The knockdown of Cdc20 dramatically inhibited tumor growth both in vivo and in vitro. Therefore, our studies delineated the oncogenic role of CDC20 and its prognostic significance at the pan-cancer level and proved its functional activity in Cdc20 high expression cancer types. Our studies will merits further molecular assays to understand the potential role of Cdc20 in tumorigenesis and provide the rationale for developing novel therapeutic strategies.

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

“…The list of CDC20 interactors is enriched for genes involved in different cell cycle phases, from G1/S to G2/M transition and from DNA damage response to anaphase-promoting complex-dependent catabolic process (Table S 1 , adjusted p < 0.001, KEGG 2021 and Gene Ontology Biological processes pathways 2021, https://amp.pharm.mssm.edu/Enrichr/ [ 78 ]). The expression levels of some interactors ( BUB1 , CCNA2 , CCNB1 , CDK1 , MAD2L1 , and PLK1 ) were positively correlated with CDC20 in cancer cells [ 10 ]. Moreover, the list of interactors included some APC/C CDC20 substrates, that are also critical cell cycle regulators, as Securin (PTTG1) [ 79 ], CCNB1 [ 80 ], CCNA1/2 [ 81 , 82 ], NEK2 [ 83 , 84 ], Zwint-1 [ 85 ] and p21 [ 86 ], indicating an APC/C-mediated role of CDC20 in cell cycle progression and chromosome segregation.…”

“…Recently, CDC20 expression has been also associated with immune infiltration in cancer. A positive correlation has been demonstrated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells across several cancer types [ 10 ], with an immune risk score based on enrichment of 2 T helper cells, memory B cells and plasmacytoid dendritic cells in lower-grade glioma [ 113 ], with the infiltration of CD8 + T cells, monocytes [ 114 , 115 ], exhausted T cells [ 114 ], CD4 + T cells, regulatory T cells, B lymphocytes, and natural killer cells [ 115 ] in hepatocellular carcinoma.…”

“…Recently, there is different evidence which suggest that CDC20 contributes to a number of cellular processes that have been partially explored. An overexpression and/or oncogenic role of CDC20 has been already described in a variety of human solid tumors [ 9 , 10 ] including pancreas [ 11 , 12 ], breast [ 13 , 14 ], lung [ 15 , 16 ], prostate [ 17 – 19 ], gastric, colorectal [ 16 , 18 ], hepatocellular [ 20 , 21 ], kidney [ 22 ], ovarian cancer [ 23 , 24 ], osteosarcoma [ 25 – 27 ] and glioblastoma [ 28 , 29 ]. Moreover, CDC20 expression level has been reported as a putative marker of clinical outcome in many cancer types, being associated with advanced stage, high grade and poor prognosis [ 9 , 10 , 30 , 31 ].…”

Identification of hub genes associated with bladder cancer using bioinformatic analyses

“…Various studies have reported the association of CDC20 with the occurrence and development of different tumors, including BLCA ( 41 ). In most cancer types, CDC20 expression is positively correlated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells ( 41 ).…”

“…Various studies have reported the association of CDC20 with the occurrence and development of different tumors, including BLCA ( 41 ). In most cancer types, CDC20 expression is positively correlated with the infiltration of cancer-associated fibroblasts and myeloid-derived suppressor cells ( 41 ). Our analysis of the relationship between CDC20 and tumor immunity revealed that CDC20 decreased CD8 + T cell, CD4 + T cell, and dendritic cell enrichment in BLCA.…”