Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma

Jingrong Xian1,2,3,4; Shiwen Wang1,2,3,4; Yanyu Jiang2; Lihui Li2; Lili Cai2; Ping Chen5; Yue Liu1,2,3,4; Xiaofei Zeng6; Guoan Chen6; Chen Ding7,8; Robert M Hoffman9,10; Lijun Jia2; Hu Zhao1,3,4; Yanmei Zhang1,3,4

2021-05

10.20892/j.issn.2095-3941.2020.0484

Cancer Biology & Medicine   影响因子和分区

2095-3941

Objective: The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target. We aimed to study whether NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) might serve as a therapeutic target in esophageal squamous cell carcinoma (ESCC).

Methods: The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas (TCGA) database and tissue arrays. NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms. Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways. The cell cycle and apoptosis were assessed with fluorescence activated cell sorting. A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.

Results: NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC, and NEDD8 overexpression was associated with poorer overall patient survival (mRNA level: P = 0.028, protein level: P = 0.026, log-rank test). Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo. Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest, DNA damage, and apoptosis in ESCC cells. Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases (CRLs) substrates through inactivation of CRLs, thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC. Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.

Nedd8 Anticancer Target Apoptosis Cullin-ring E3 Ubiquitin Ligases Esophageal Squamous Cell Carcinoma.

SCI

英语

其他

National Natural Science Foundation of China[81602072,81902380,81820108022,81625018] ; Innovation Program of Shanghai Municipal Education Commission[2019-01-0700-10-E00056] ; Program of Shanghai Academic/Technology Research Leader[18XD1403800] ; National High Technology Research and Development Program of China[2015AA021107-019] ; Scientific Research Project of Shanghai Science and Technology Commission[18411960600] ; Shanghai Technological Innovation Action Projects[18411950800] ; Shanghai Sailing Program[17YF1405000]

Oncology ; Research & Experimental Medicine

Oncology ; Medicine, Research & Experimental

WOS:000729405300001

CHINA ANTI-CANCER ASSOC

人工提交

1.Department of Laboratory Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
2.Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
3.Research Center on Aging and Medicine, Fudan University, Shanghai 200040, China.
4.Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, China.
5.Department of Basic Science of Oncology, College of Basic Medical Sciences, Zhengzhou University, Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450001, China.
6.School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
7.State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
8.State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang 453007, China.
9.Department of Surgery, University of California, San Diego 92101, USA.
10.Anticancer Inc., San Diego 92101, USA.

Jingrong Xian,Shiwen Wang,Yanyu Jiang,et al. Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma[J]. Cancer Biology & Medicine,2021.

Jingrong Xian.,Shiwen Wang.,Yanyu Jiang.,Lihui Li.,Lili Cai.,...&Yanmei Zhang.(2021).Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma.Cancer Biology & Medicine.

Jingrong Xian,et al."Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma".Cancer Biology & Medicine (2021).