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Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4

查看全文 作　　者：Ting [1]Guo;Yan-Hua [2]Bai;Xiao-Jing [1]Cheng;Hai-Bo [3]Han;Hong [1]Du;Ying [3]Hu;Shu-Qin [4]Jia;Xiao-Fang [1]Xing;Jia-Fu [1,5]Ji 高影响力作者 机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Division of Gastrointestinal Cancer Translational Research Laboratory,Peking University Cancer Hospital&Institute,Beijing 100142,P.R.China;[2]Department of Pathology,Peking University Cancer Hospital&Institute,Beijing 100142,P.R.China;[3]The Tissue Bank,Peking University Cancer Hospital&Institute,Beijing 100142,P.R.China;[4]Department of Molecular Diagnosis,Peking University Cancer Hospital&Institute,Beijing 100142,P.R.China;[5]Department of Gastrointestinal Surgery,Peking University Cancer Hospital&Institute,Beijing 100142,P.R.China高影响力机构 出　　处：《Cancer Communications》索引2021年第41卷第3期,共15页高影响力期刊 基　　金：Natural Science Foundation of Beijing,Grant/Award Number:7132051;National Natural Science Foundation of China,Grant/Award Numbers:81301874,81972758,81872502,81802471;Interdisciplinary Medicine Seed Fund of Peking University,Grant/Award Number:BMU2018MX018;Beijing Municipal Administration of Hospitals’Youth Program,Grant/Award Number:QML20181102;National High Technology Research and Development Program of China,Grant/Award Number:2014AA020603;Science Foundation of Peking University Cancer Hospital,Grant/Award Numbers:2017-23,2020-6。 摘　　要：Background:Insulin gene enhancer protein 1,(ISL1),a LIM-homeodomain transcription factor,is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes.However,the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer(GC)is unclear.In this study,we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis.Methods:We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real-time polymerase chain reaction(PCR).Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown.RNA-sequencing was performed to identify differentially expressed genes,followed by Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis and Gene Set Enrichment Analysis(GSEA)to reveal key signaling pathways likely regulated by ISL1 in GC.Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)and by detecting glucose consumption and lactate production.The expression of glucose transporter 4(GLUT4)and ISL1 was assessed by Western blotting,immunohistochemistry,and immunofluorescent microscopy.The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4.Results:High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients.ISL1 knockdown inhibited cell proliferation both in vitro and in vivo.KEGG analysis and GSEA for RNA-sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown,which was validated by reduced glucose uptake and lactate production,decreased ECAR,and increased OCR.Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter.Conclusion:ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4. 关 键 词：gastric cancer glucose transporter 4 GLYCOLYSIS insulin gene enhancer protein 1 TUMORIGENESIS
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