|Table of Contents|

To explore the role and mechanism of Nrf3 in the proliferation and migration of gastric cancer cells by cellular metabolomics

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 07
Page:
1186-1193
Research Field:
Publishing date:

Info

Title:
To explore the role and mechanism of Nrf3 in the proliferation and migration of gastric cancer cells by cellular metabolomics
Author(s):
CHEN Mengwei1; CHEN Yahui1; HOU Wei2; HU Qingyong1; ZHOU Qianru1; TANG Jiancai1
1.Institute of Basic Medicine and Forensics Medicine;2.Department of Pathology,North of Sichuan Medical College,Sichuan Nanchong 637000,China.
Keywords:
gastric cancer; Nrf3; choline metabolism; proliferation and migration
PACS:
R735.2
DOI:
10.3969/j.issn.1672-4992.2024.07.002
Abstract:
Objective:To investigate the effect of nuclear factor red lineage-like 3(NF-E2-related factor 3 or NFE2L3,Nrf3) on the metabolism,proliferation and migration of gastric cancer cells and its mechanism.Methods:The expression of Nrf3 in gastric cancer tissues was analyzed by bioinformatics.Lentivirus was constructed to silence Nrf3 gene in gastric cancer cell line.Based on human cell UHPLC-OE-MS non-target metabolomic technique,the metabolomic profiles of gastric cancer cells(AGS) and Nrf3 knock-down cells were analyzed.The effect of knockdown of Nrf3 on the key enzymes of choline metabolism was detected by RT-qPCR and Western blot.The effects of knockdown of Nrf3 on proliferation and migration of gastric cancer cells were examined by CCK-8 and scratch test.The changes of proliferation and migration of gastric cancer cells were observed after exogenous administration of choline analogue choline chloride.Results:The expression of Nrf3 in gastric carcinoma was higher than that in adjacent tissues by bioinformatics analysis.Knockdown of Nrf3 significantly altered the metabolic profile of gastric cancer cells,identifying 57 differential metabolites that contributed significantly to classification,of which 25 metabolites were decreased and 23 metabolites were increased in gastric cancer cells knockdown of Nrf3.Knockdown of Nrf3 resulted in the alteration of 8 pathways in gastric cancer cells(P＜0.05),among which the changes of choline,arginine and proline metabolism were the most obvious(P＜0.01).The results of RT-qPCR and Western blot showed that knockdown of Nrf3 affected the expression of PLA2,LYPLA1,GPCPD1 and CHK,especially GPCPD1.The results of CCK-8,and scratch experiments revealed that knockdown of Nrf3 inhibited the proliferation and migration of gastric cancer cells.Exogenous administration of cholinergic chloride partially reversed the inhibition of proliferation and migration induced by knockdown of Nrf3 in gastric cancer cells.Conclusion:Knockdown of Nrf3 inhibits the proliferation and migration of gastric cancer cells,which may be related to the reprogramming of choline metabolism.

References:

［1］SUNG H,FERLAY J,SIEGEL RL,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］.CA Cancer J Clin,2021,71(3):209-249.
［2］XIA C,DONG X,LI H,et al.Cancer statistics in China and United States,2022:Profiles,trends,and determinants［J］.Chin Med J(Engl),2022,135(5):584-590.
［3］LI X,XU J,XIE J,et al.Research progress in targeted therapy and immunotherapy for gastric cancer［J］.Chin Med J(Engl),2022,135(11):1299-1313.
［4］KOBAYASHI A.Roles of NRF3 in the Hallmarks of cancer:Proteasomal inactivation of tumor suppressors［J］.Cancers(Basel),2020,12(9):2681.
［5］CHEVILLARD G,BLANK V.NFE2L3(NRF3):The cinderella of the cap 'n' collar transcription factors［J］.Cell Mol Life Sci,2011,68(20):3337-3348.
［6］NOUHI Z,CHEVILLARD G,DERJUGA A,et al.Endoplasmic reticulum association and N-linked glycosylation of the human Nrf3 transcription factor［J］.FEBS Lett,2007,581(28):5401-5406.
［7］CAI BQ,CHEN WM,ZHAO J,et al.Nrf3 promotes 5-FU resistance in colorectal cancer cells via the NF-kappaB/BCL-2 signaling pathway in vitro and in vivo［J］.J Oncol,2021,2021：9355555.
［8］CHOWDHURY A,KATOH H,HATANAKA A,et al.Multiple regulatory mechanisms of the biological function of NRF3(NFE2L3) control cancer cell proliferation［J］.Sci Rep,2017,7(1):12494.
［9］KOBAYASHI A,WAKU T.New addiction to the NRF2-related factor NRF3 in cancer cells:Ubiquitin-independent proteolysis through the 20S proteasome［J］.Cancer Sci,2020,111(1):6-14.
［10］BURY M,LE CALVE B,LESSARD F,et al.NFE2L3 controls colon cancer cell growth through regulation of DUX4,a CDK1 inhibitor［J］.Cell Rep,2019,29(6):1469-1481 e9.
［11］AONO S,HATANAKA A,HATANAKA A,et al.β-Catenin/TCF4 complex-mediated induction of the NRF3(NFE2L3) gene in cancer cells［J］.Int J Mol Sci,2019,20(13):3344.
［12］QIAN J,HUANG C,ZHU Z,et al.NFE2L3 promotes tumor progression and predicts a poor prognosis of bladder cancer［J］.Carcinogenesis,2022,43(5):457-468.
［13］WANG C,SAJI M,JUSTINIANO SE,et al.RCAN1-4 is a thyroid cancer growth and metastasis suppressor［J］.JCI Insight,2017,2(5):e90651.
［14］WANG H,ZHAN M,YANG R,et al.Elevated expression of NFE2L3 predicts the poor prognosis of pancreatic cancer patients［J］.Cell Cycle,2018,17(17):2164-2174.
［15］HANAHAN D.Hallmarks of cancer:New dimensions［J］.Cancer Discov,2022,12(1):31-46.
［16］ECKER J,LIEBISCH G.Application of stable isotopes to investigate the metabolism of fatty acids,glycerophospholipid and sphingolipid species［J］.Prog Lipid Res,2014,54:14-31.
［17］TROUSIL S,LEE P,PINATO DJ,et al.Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway［J］.Cancer Res,2014,74(23):6867-6877.
［18］来嘉伟，程永毅，周建成.代谢组学和肾癌中代谢重编程的研究进展［J］.现代肿瘤医学，2022，30（17）：3217-3220. LAI JW,CHENG YY,ZHOU JC.Progress in metabonomics and metabolic reprogramming in renal cell carcinoma［J］.Modern Oncology，2022，30（17）：3217-3220.
［19］KELLER M,ROHLF K,GLOTZBACH A,et al.Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth［J］.J Exp Clin Cancer Res,2023,42(1):25.
［20］MARCHAN R,LESJAK MS,STEWART JD,et al.Choline-releasing glycerophosphodiesterase EDI3 links the tumor metabolome to signaling network activities［J］.Cell Cycle,2012,11(24):4499-4506.
［21］GADIYA M,MORI N,CAO MD,et al.Phospholipase D1 and choline kinase-alpha are interactive targets in breast cancer［J］.Cancer Biol Ther,2014,15(5):593-601.
［22］STEWART JD,MARCHAN R,LESJAK MS,et al.Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis［J］.Proc Natl Acad Sci USA,2012,109(21):8155-8160.
［23］LESJAK MS,MARCHAN R,STEWART JD,et al.EDI3 links choline metabolism to integrin expression,cell adhesion and spreading［J］.Cell Adh Migr,2014,8(5):499-508.

Memo

Memo:
四川省南充市科技局项目(编号：20SXCXTD004);川北医学院重点培育项目(编号：CBY22-ZDA-02)
Last Update: 2024-02-29