CDCA2 promotes lung adenocarcinoma cell proliferation and predicts poor survival in lung adenocarcinoma patients.

Run Shi,Xin Wang,Qi Sun,Gaochao Dong,Lin Xu,Jing Sun,Chunrong Zhang,Wenjie Xia,Feng Jiang,Anpeng Wang,Yaqin Wu

doi:10.18632/oncotarget.15519

Abstract

Cell division cycle associated 2(CDCA2) is overexpressed in neuroblastoma and oral squamous cell carcinoma, and its overexpression positively correlates to tumor progression. However, the biological and clinical significance of CDCA2 in lung adenocarcinoma(LAC) has never been investigated. We determined the expression profile and clinical significance of CDCA2 using The Cancer Genome Atlas(TCGA) and tissue microarray(TMA). Furthermore, we explored the biological function of CDCA2 both in vitro and in vivo. A great upregulation of CDCA2 was observed in LAC tissues compared with adjacent normal tissues. Importantly, Cox regression analysis indicated that high level of CDCA2 was an independent risk factor for overall survival(OS) in LAC patients (TCGA: HR = 1.720, p = 0.004; TMA: HR = 1.971, p = 0.023). Inhibition of CDCA2 suppressed the proliferation of LAC cells via G1 phase arrest by downregulating cyclin E1(CCNE1), while overexpression of CDCA2 promoted LAC cells proliferation by upregulating CCNE1. Moreover, the oncogenic activity of CDCA2 was also confirmed in vivo. In conclusion, CDCA2 promotes proliferation of LAC cells and predicts poor prognosis in LAC patients. CDCA2 might play a significant role in LAC progression.

Highlights

Lung cancer is the most common malignancy and the leading cause of cancer-related death worldwide [1]
Peng et al reported that the level of CDCA2 determined the activation threshold of the DNA damage checkpoint [4]
Vagnarelli et al reported that CDCA2 acts as a key regulator in chromatin remodeling by targeting PP1 for the de-phosphorylation of histone H3 [8]

Summary

Introduction

Lung cancer is the most common malignancy and the leading cause of cancer-related death worldwide [1]. Two main histological types are included: non-small cell lung cancer(NSCLC) and small cell lung cancer. NSCLC constitutes about 85% of all lung cancers, and lung adenocarcinoma(LAC) has been the most common subtype of NSCLC in recent years [1, 2]. Despite advances in lung cancer therapies, prognosis of NSCLC is still unfavorable, with an overall 5-year survival rate less than 15% [3]. Cell division cycle associated 2(CDCA2), a nuclear protein that binds to protein phosphatase 1 γ(PP1γ), regulates the DNA damage response(DDR) in cell cycle [4, 5]. CDCA2-PP1γ complex cooperates with condensin to preserve the characteristic chromosome architecture during mitosis [6], and the complex is an anaphaseactivated protein phosphatase that is regulated via CDCA2 phosphorylation [7]. Though CDCA2 is overexpressed in aggressive neuroblastoma [9] and oral squamous cell carcinoma [10], the expression profile and biological function of CDCA2 in NSCLC still remain unknown

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