The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the ear...The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.展开更多
目的探讨叉头框转录因子A2(FOXA2)对肝癌细胞迁移和侵袭能力的影响。方法 Western Blot检测多种肝癌细胞系中FOXA2和E钙黏蛋白(E-cadherin)表达水平,应用FOXA2表达质粒和空白对照质粒(EV)转染MHCC-97H细胞,Transwell小室检测肿瘤细胞迁...目的探讨叉头框转录因子A2(FOXA2)对肝癌细胞迁移和侵袭能力的影响。方法 Western Blot检测多种肝癌细胞系中FOXA2和E钙黏蛋白(E-cadherin)表达水平,应用FOXA2表达质粒和空白对照质粒(EV)转染MHCC-97H细胞,Transwell小室检测肿瘤细胞迁移和侵袭能力变化。结果 FOXA2和E-cadherin在高侵袭的MHCC-97H细胞中表达最高,而在低侵袭的Hep G2细胞中表达最低,过表达FOXA2上调MHCC-97H细胞中E-cadherin蛋白水平[(0.10±0.03)比(0.37±0.06),P<0.001]。另外,过表达FOXA2显著抑制MHCC-97H细胞迁移和侵袭能力(P<0.001)。结论 FOXA2在高侵袭性的肝癌细胞中低表达,过表达FOXA2上调E-cadherin表达水平且抑制MHCC-97H细胞迁移和侵袭,提示FOXA2可能在肝细胞癌侵袭转移过程中发挥重要作用。展开更多
Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
基金The National Natural Science Foundation of China,Nos.30871118,30971325,81270129 and 81470268(FL)grants from Department of Science and Technology of Sichuan Province,Nos.09ZQ026-020 and 2009SZ0190(FL)
文摘The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
