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On-line Access: 2022-10-12

Received: 2022-03-18

Revision Accepted: 2022-06-02

Crosschecked: 2022-10-13

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Hailong PIAO

https://orcid.org/0000-0001-7451-0386

Chundong GU

https://orcid.org/0000-0002-2981-6578

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Journal of Zhejiang University SCIENCE B

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UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis


Author(s):  Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU

Affiliation(s):  Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; more

Corresponding email(s):  guchundong@dmu.edu.cn, hpiao@dicp.ac.cn

Key Words:  Up-frameshift 1 (UPF1); Activating transcription factor 4 (ATF4); Amino acid metabolism; Lung adenocarcinoma


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Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU. UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200144

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author="Lei FANG, Huan QI, Peng WANG, Shiqing WANG, Tianjiao LI, Tian XIA, Hailong PIAO, Chundong GU",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200144"
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%T UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis
%A Lei FANG
%A Huan QI
%A Peng WANG
%A Shiqing WANG
%A Tianjiao LI
%A Tian XIA
%A Hailong PIAO
%A Chundong GU
%J Journal of Zhejiang University SCIENCE B
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doi="https://doi.org/10.1631/jzus.B2200144"

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A1 - Shiqing WANG
A1 - Tianjiao LI
A1 - Tian XIA
A1 - Hailong PIAO
A1 - Chundong GU
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Abstract: 
Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.

UPF1通过调控eIF2α-ATF4通路提高细胞内氨基酸水平促进肺腺癌增殖

房磊1,齐欢2,王鹏1,王世晴1,李天娇1,夏天2,朴海龙2,顾春东1
1大连医科大学附属第一医院胸外科,大连市肺癌诊疗中心,中国大连,116011
2中国科学院分析化学分离科学重点实验室,中国科学院大连化学物理研究所,中国大连,116023
目的:UPF1是调节无义介导的mRNA降解的核心因子,参与多种肿瘤进展相关分子通路的调节,其在肺腺癌氨基酸代谢中的作用尚不清楚。
方法和结果:本研究通过结合生物信息学和代谢组学,分析发现UPF1与肺腺癌中部分氨基酸代谢通路显著相关,证实UPF1敲低后可显著抑制氨基酸代谢重编程核心蛋白ATF4的表达及eIF2α-Ser51位点的磷酸化水平,且UPF1通过调控ATF4蛋白增加肺腺癌细胞的氨基酸水平进而促进细胞增殖。在临床患者样本数据库中,肺腺癌组织中UPF1的mRNA水平表达异常,UPF1和ATF4均高表达的肺腺癌患者有着较差的总生存期。
结论:本研究表明,UPF1是肿瘤氨基酸代谢重编程的潜在调控因子,可作为肺腺癌治疗的新靶点。

关键词组:UPF1;ATF4;氨基酸;肺腺癌

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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