Knockdown of ATAD2 Inhibits Proliferation and Tumorigenicity Through the Rb-E2F1 Pathway and Serves as a Novel Prognostic Indicator in Gastric Cancer

Xuan Zhou; Huihui Ji; Dongxue Ye; Hong Li; Fen Liu; Haiyan Li; Jin Xu; Yujun Li; Fenggang Xiang

doi:10.2147/CMAR.S228629

Knockdown of ATAD2 Inhibits Proliferation and Tumorigenicity Through the Rb-E2F1 Pathway and Serves as a Novel Prognostic Indicator in Gastric Cancer

Cancer Manag Res. 2020 Jan 15:12:337-351. doi: 10.2147/CMAR.S228629. eCollection 2020.

Authors

Xuan Zhou^#¹, Huihui Ji^#², Dongxue Ye², Hong Li¹, Fen Liu², Haiyan Li², Jin Xu¹, Yujun Li¹, Fenggang Xiang^{1

2}

Affiliations

¹ Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266000, People's Republic of China.
² Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: The aim of the present study was to examine the expression of ATAD2 in gastric cancer (GC) specimens and to evaluate its correlation with clinicopathologic features, including survival of GC patients. The potential roles of ATAD2 in the GC cell proliferation, apoptosis, and tumour growth were further explored.

Materials and methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were applied to determine the mRNA and protein expression of ATAD2 in GC and corresponding adjacent non-tumourous specimens. The relationship between ATAD2 expression and clinicopathological features of GC patients was analysed. Kaplan-Meier analysis was performed to assess the prognostic value of ATAD2 expression levels. The proliferation, colony formation, apoptosis and tumorigenesis roles of ATAD2 were measured using in vitro and in vivo experiments.

Results: The expression of ATAD2 mRNA and protein was overexpressed in GC tissues compared with corresponding adjacent non-tumourous tissues. ATAD2 expression was significantly correlated with tumour size, tumour differentiation, and clinical tumour-node-metastasis (TNM) stage. Patients with high ATAD2 expression were likely to experience significantly shorter postoperative overall survival (OS) and disease-free survival (DFS). Multivariate Cox analysis suggested ATAD2 as an independent variable for OS and DFS. Knockdown of ATAD2 significantly suppressed cell proliferation, colony formation in vitro and tumorigenicity in vivo. Cell cycle and apoptotic assays showed that the anti-proliferative effect of pLV-ATAD2 shRNA was mediated by arresting cells in the G1 phase and inducing cell apoptosis. Silencing of ATAD2 reduced the expression of cyclinD1, ppRb, E2F1 and cyclinE and upregulated the expression of cleaved-PARP and cleaved-Caspase 3.

Conclusion: Our study indicated that ATAD2 plays an important role in the process of tumorigenesis and progression in GC, and it could serve as a novel prognostic biomarker and a therapeutic target for the treatment of GC patients.

Keywords: ATAD2; apoptosis; gastric cancer; prognosis; proliferation.