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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2020, Vol. 14 Issue (3) : 318-326    https://doi.org/10.1007/s11684-019-0708-6
RESEARCH ARTICLE
Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer
Yanfei Zhang1,2,3, Xinchun Zhao4, Yongchun Zhou5, Min Wang1,2, Guangbiao Zhou1,2,3()
1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3. University of Chinese Academy of Sciences, Beijing 100049, China
4. School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
5. Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China
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Abstract

In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells. We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.

Keywords RFWD3      NSCLC      prognosis      tobacco smoke     
Corresponding Author(s): Guangbiao Zhou   
Just Accepted Date: 08 August 2019   Online First Date: 09 October 2019    Issue Date: 08 June 2020
 Cite this article:   
Yanfei Zhang,Xinchun Zhao,Yongchun Zhou, et al. Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer[J]. Front. Med., 2020, 14(3): 318-326.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0708-6
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/318
Fig.1  RFWD3 is required for NSCLC cell proliferation. (A) Schematic of the study workflow. (B) Z-scores of siRFWD3 in A549 and H1975 cells treated with 50 nmol/L indicated siRNAs from the siGenome library (containing 696 UPGs) for 72 h. (C) The cells were transfected with siRFWD3, transfection efficacy was tested using real-time RT-PCR and Western blot analysis, and cell proliferation was assessed by CCK-8 analysis. (D) Colony-forming activity of the cells transfected with siNC or siRFWD3.
Characteristics Cases, n RFWD3-high, n (%) P values*
Total number 22 14 (64)
Histology
Adenocarcinoma 17 11 (64.7) 0.519
Squamous cell carcinoma 5 4 (80)
Smoking
Smoker 10 9 (90) 0.019
Non-smoker 12 6 (50)
TNM stage
I–II 12 8 (66.7) 0.87
III–IV 10 7 (70)
Tab.1  Baseline demographic characteristics of 22 patients
Fig.2  RFWD3 in NSCLCs. (A) The expression of RFWD3 in tumor samples was detected by immunohistochemistry assay with an anti-RFWD3 antibody. Scale bar, 500 µm. (B) Immunoreactivity of RFWD3 among patients.
Fig.3  Expression of RFWD3 in NSCLCs in Oncomine and TCGA datasets. Expression of RFWD3 in Oncomine datasets Hou Lung (A), Selamat Lung (B), Landi Lung (C), Okayama Lung (D), Wachi Lung (E), and Su Lung (F); and TCGA NSCLC (G), LUAD (H), and LUSC (I). (J, K) RFWD3 in tumor samples and adjacent normal lung tissues of TCGA LUAD (J) and LUSC (K).
Fig.4  Expression of RFWD3 in Asian NSCLCs in GEO datasets. (A) Expression of RFWD3 in Chinese NSCLCs and (B) in Japanese NSCLCs.
Fig.5  OS of NSCLCs with high or low levels of RFWD3 expression. (A) Kaplan–Meier survival curves of NSCLCs, LUADs, and LUSCs of the Online Survival Analysis software. (B) Survival results of TCGA NSCLCs whose tumor-adjacent samples were analyzed for RFWD3 expression in their transcriptome datasets.
Fig.6  RFWD3 expression in smoker and non-smoker NSCLCs in the datasets of Oncomine Lee Lung (A), TCGA (B), and GEO Sweden Lung (C).
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