Increased CDC 20 expression is associated with development and progression of hepatocellular carcinoma

Cell division cycle 20 (CDC20) encodes a regulatory protein interacting with the anaphase-promoting complex/cyclosome (APC/C) in the cell cycle and plays important roles in tumorigenesis and progression of multiple tumors. The present study aimed to investigate the clinical significance of CDC20 in hepatocellular carcinoma (HCC) and the role of CDC20 in the progression of HCC. By bioinformatics analysis, CDC20 was found to be the major node in HCC molecular interaction networks. Quantitative PCR and western blot analyses were applied to examine CDC20 expression in 16 paired primary HCC tissues. Immunohistochemistry (IHC) was performed to examine CDC20 protein expression in 132 matched paraffinembedded HCC tissues and to analyze the relationship between CDC20 staining and clinical characteristics. Small interfering RNA (siRNA) targeting CDC20 was synthesized and transfected into HepG2 cells to investigate the role of CDC20 in cell growth and the cell cycle. Results show that CDC20 expression was upregulated in HCC tissues compared to adjacent non-tumor liver tissues. In the 132 matched HCC tissues, high expression levels of CDC20 were detected in 68.18% HCC samples, and overexpression of CDC20 was positively correlated with gender (P=0.013), tumor differentiation (P=0.000), TNM stage (P=0.012), P53 and Ki-67 expression (P=0.023 and P=0.007, respectively). Cells transfected with CDC20 siRNA showed a decrease in cell proliferation and increase in the number of cells in G2/M-phase. In conclusion, increased expression of CDC20 was demonstrated to be associated with the development and progression of HCC, and may be regarded as a promising therapeutic target for HCC. Introduction Hepatocellular carcinoma (HCC) which represents the major histological subtype of primary liver cancers, is the fifth most frequent cancer worldwide and the third leading cause of cancer mortality (1,2). The highest liver cancer rates are found in developing countries especially in East/South-East Asia and Middle/ Western Africa, whereas rates are low in South-Central, Western Asia, Northern and Eastern Europe (3). Genetic alteration and epigenetic high-risk factors such as chronic infection with HBV or HCV, hepatic cirrhosis, alcoholic liver disease and aflatoxins account for the high morbidity of HCC (4-6). However, the molecular mechanism accompanied by hepatocarcinogenesis and progression is still largely unclear. Thus, it is critical for us to clarify the etiology and investigate the vitally molecular alteration underlying hepatocellular carcinoma initiation and progression, and ultimately improve our current concepts for diagnosing, screening and treatment of this disease. During the process of hepatocarcinogenesis, the abrogation of cell-cycle checkpoints is an important hallmark that may promote cancer formation (2). As one of the regulators of the cell cycle checkpoint, cell division cycle 20 (CDC20) appears to act as a regulatory protein interacting with the anaphasepromoting complex/cyclosome (APC/C) in the cell cycle, which is required for anaphase initiation and late mitosis exit (7,8). Two regulatory factors, CDC20 and CDH1 directly bind to APC and activate its cyclin ubiquitination activity during mitosis and G1 phase (9,10). It has been reported that the receptor-associated protein 80 (RAP80), which recruits BRCA1 to DNA damage sites in the ubiquitin signaling pathway induced by DNA damage, can be degraded by the anaphase-promoting complex (APC/C-Cdc20) or (APC/C-Cdh1) through polyubiquitination during mitosis to the G1 phase (11). The depletion of RAP80 showed a defective control of G2-M phase checkpoint and promoted mitotic cell cycle progression. CDC20 expression can be remarkably suppressed by p53 protein which inhibits malignant transformation through regulation of the cell cycle, cellular senescence and apoptosis related genes (12). High expression of CDC20 has been reported in various malignant tumors including pancreatic ductal adenocarcinoma (13), oral squamous cell carcinoma, gastric cancer (14), cervical cancer (15) and various cancer Increased CDC20 expression is associated with development and progression of hepatocellular carcinoma JIA LI1,2, JIAN-ZHI GAO1,4, JING-LI DU1, ZHONG-XI HUANG3* and LI-XIN WEI1* 1Department of Pathology, Chinese PLA General Hospital, Beijing 100853; 2Department of Clinical Medicine, Medical College, Nankai University, Tianjing 300071; 3Cancer Institute, Southern Medical University, Guangzhou, Guangdong 510515; 4Department of Basic Medical Sciences, Xinxiang Medical College, Xinxiang 453000, P.R. China Received February 13, 2014; Accepted April 22, 2014 DOI: 10.3892/ijo.2014. 2559 Correspondence to: Professor Li-Xin Wei, Department of Pathology, Chinese PLA General Hospital, Beijing 100853, P.R. China E-mail: weilx301@263.net *Contributed equally