1.Expression and Clinical Significance of ATP Citrate Lyase in Hepatocellular Carcinoma.
Hua-Jing YU ; Lu-Yang WEI ; Shan-Shan LIU ; Zhong-Tao ZHANG ; Cheng-Jian GUAN
Acta Academiae Medicinae Sinicae 2023;45(5):743-751
Objective To investigate the role of ATP citrate lyase(ACLY)in the development of hepatocellular carcinoma(HCC)and the impact of this enzyme on the immune microenvironment of HCC.Methods We utilized the University of Alabama at Birmingham Cancer Data Analysis Portal and the Gene Expression Profiling Interactive Analysis to identify the changes in ACLY expression and prognosis across different tumor types from The Cancer Genome Atlas.With HCC as the disease model,we analyzed the ACLY expression in HCC samples from the gene expression database.Furthermore,we collected the clinical specimens from HCC patients to verify the mRNA and protein levels of ACLY.In addition,we conducted transcriptome sequencing after knocking down the expression of ACLY to analyze the differentially expressed genes and investigated the impact of ACLY expression interference on cell proliferation and other functions.Finally,we explored the correlations of ACLY with immune cells and immune infiltration in the tumor microenvironment,new antigens,and immune checkpoint genes.Results ACLY expression was significantly up-regulated in solid tumors including HCC(all P<0.05),and high ACLY expression was associated with overall survival rate in HCC(P=0.005).Furthermore,high ACLY expression affected the presence of immune cells(e.g.,tumor-associated fibroblasts)and the expression of genes involved in lipid metabolism(all P<0.05).Conclusions ACLY is closely related to the occurrence and development of HCC and lipid metabolism abnormalities.Moreover,it has a specific impact on the immune microenvironment of HCC.
Humans
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ATP Citrate (pro-S)-Lyase/metabolism*
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Carcinoma, Hepatocellular
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Clinical Relevance
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Lipid Metabolism
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Liver Neoplasms
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Tumor Microenvironment
2.Characterization of regulatory elements on the promoter region of human ATP-citrate lyase.
Young Ah MOON ; Kyung Sup KIM ; Un Hyung CHO ; Do Jun YOON ; Sahng Wook PARK
Experimental & Molecular Medicine 1999;31(2):108-114
ATP-citrate lyase (ACL), an enzyme catalyzing the first step in biosynthesis of fatty acids, is induced during the lipogenesis and cholesterologenesis. We demonstrate that the region -213 to -128 of human ACL promoter is responsible for conferring glucose-mediated transcription. This region in the ACL promoter contains Sp1 binding sites determined by DNase I foot-printing assay. Gel retardation assay using oligonucleotides from -179 to -141 and -140 to -110 showed two specific DNA-protein complexes postulated to be formed by transcription factor Sp1. Competition gel shift and supershift assays have confirmed that these DNA-protein complexes were the result of induced Sp1 as well as another Sp1-related proteins. Western blot analysis also demonstrated that transcription factor Sp1 was slightly increased in the nuclear proteins extracted from Alexander cells following supplementation of glucose. In addition, expression of 110 kDa protein reacting with antibody against Sp3 was dramatically increased by glucose supplementation, while isoforms of Sp3, about 80 kDa in size was decreased in its amounts. Our results suggest that changes in the expression of Sp1 family proteins play an important role in activation of the ACL promoter by glucose.
ATP Citrate (pro-S)-Lyase/metabolism
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ATP Citrate (pro-S)-Lyase/genetics*
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Binding Sites
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Cells, Cultured
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Chloramphenicol O-Acetyltransferase/genetics
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DNA Footprinting/methods
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Deoxyribonuclease I/metabolism
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Electrophoresis, Polyacrylamide Gel
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Gene Expression Regulation, Enzymologic*
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Glucose/pharmacology
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Glucose/metabolism*
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Human
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Immunoblotting
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Promoter Regions (Genetics)*
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Transcription Factor, Sp1/metabolism*
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Transcription, Genetic*
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Transfection