Identification of CDCA2 as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma

Zhenjun Yu; Yu Zhang; Shuai Shao; Qi Liu; Yuhan Li; Xiaoxiao Du; Kun Zhang; Mengxia Zhang; Haixia Yuan; Qiang Yuan; Tong Liu; Yingtang Gao; Yijun Wang; Wei Hong; Tao Han

doi:10.3389/fonc.2021.755814

Identification of CDCA2 as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma

Front Oncol. 2021 Oct 1:11:755814. doi: 10.3389/fonc.2021.755814. eCollection 2021.

Authors

Zhenjun Yu^{1

2}, Yu Zhang^{1

2}, Shuai Shao³, Qi Liu², Yuhan Li^{1

2}, Xiaoxiao Du², Kun Zhang², Mengxia Zhang², Haixia Yuan¹, Qiang Yuan⁴, Tong Liu⁵, Yingtang Gao⁵, Yijun Wang⁴, Wei Hong², Tao Han^{1

2

3

5}

Affiliations

¹ Department of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical University, Tianjin, China.
² Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
³ Department of Hepatology and Gastroenterology, Tianjin Union Medical Center Affiliated to Nankai University, Tianjin, China.
⁴ Department of Hepatobiliary Surgery, The Tianjin Third Central Hospital, Tianjin, China.
⁵ Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, The Tianjin Third Central Hospital, Tianjin, China.

Abstract

Objective: Hepatocellular carcinoma (HCC) is one of the most common and malignant tumors with an insidious onset, difficult early diagnosis, and limited therapy options, resulting in a poor prognosis. Cell division cycle associated 2 (CDCA2), also known as Repo-Man, plays an important role in regulating mitosis and DNA repair, but the involvement of CDCA2 in HCC remains unclear.

Methods: The differentially expressed genes that were significantly upregulated in multiple RNA sequencing datasets of HCC were screened. Receiver operating characteristic (ROC) curve analysis was performed to identify diagnostic markers for HCC. Least absolute shrinkage and selection operator Cox regression analysis was performed to screen the prognosis-related genes. The screening and analyses identified CDCA2 as the target gene in this study. The expression of CDCA2 was analyzed in public databases and clinical specimens, and CDCA2 involvement in HCC was explored by both bioinformatic analysis and in vitro experiments.

Results: The level of CDCA2 was enhanced in HCC compared with healthy livers. Overexpression of CDCA2 positively correlated with the pathological grade and TNM stage of the diseases. Furthermore, CDCA2 was found to be an independent prognostic predictor. An excellent prognostic model of HCC was successfully constructed with CDCA2 in combination with TNM stage. Bioinformatic analysis revealed that CDCA2 was closely associated with the cell cycle, apoptosis, and p53 signaling pathway. Silencing CDCA2 in Huh7 cells resulted in significant upregulation of p53 and the downstream PUMA and NOXA and a subsequently increased apoptosis. Inhibition of p53 signaling and apoptosis was found after overexpression of CDCA2 in L02 cells. Strikingly, the proliferation of cells was not affected by CDCA2.

Conclusions: CDCA2 was a novel diagnostic marker for HCC, and overexpression of this gene reflected poor pathological grade, stage, and clinical prognosis. CDCA2 promoted the pathogenesis of HCC by suppressing the p53-PUMA/NOXA signaling and the subsequent apoptosis.

Keywords: CDCA2; bioinformatics; biomarker; hepatocellular carcinoma; prognosis.