Cell division cycle associated 2 (CDCA2) upregulation promotes the progression of hepatocellular carcinoma in a p53-dependant manner

Abstract

Background Elevated expression and oncogenic functions of cell division cycle associated 2 (CDCA2), an important mitotic regulator, have been demonstrated in several cancer types, however their involvement in hepatocellular carcinoma (HCC) has not been elucidated, and the underlying molecular mechanism remains unclear. This study aims to determine the role of CDCA2 in HCC and the underlying molecular mechanism. Methods The expression of CDCA2 in HCC was studied in 40 pairs of frozen and 48 pairs of paraffin-embedded HCC samples and paracancerous normal samples by qRT-PCR and immunohistochemistry, respectively, and using The Cancer Genome Atlas (TCGA) datasets. The cellular function of CDCA2 was studied in vitro in the HepG2, Huh7 and SK-Hep1 HCC cell lines. Results We found significantly upregulated CDCA2 expression in HCC, which was correlated with higher clinical stage, tumor grade and Glypican-3 (+). High CDCA2 expression was correlated with worse overall survival. CDCA2 promoted the proliferation of HCC cells by promoting G1/S transition through the upregulation and activation of CCND1/CDK4/6 and CCNE1/CDK2, enhanced the clonogenic ability, inhibited apoptosis in a p53/p21-dependent manner by inhibiting the p38 MAPK pathway and activating the JNK/c-Jun pathway, and promoted the migration of p53-mutant Huh7 cells by activating the epithelial-mesenchymal transition. Targeting CDCA2 reduced the chemoresistance of HCC cells to cisplatin. CDCA2 expression was also regulated by cyclophilin J. Conclusions This study revealed elevated expression of CDCA2 in HCC, possibly as a result of p53 dysregulation, which was associated with worse prognosis of patients. We confirmed the oncogenic role of CDCA2 in HCC in vitro and revealed some of the underlying molecular mechanisms. This study indicated the potential value of CDCA2 as a future target for the treatment of HCC.

Keywords

• Hepatocellular carcinoma
• Cell division cycle associated 2 protein
• TCGA datasets
• G1/S transition
• Cell proliferation
• Epithelial-mesenchymal transition