胃癌的发生是由正常胃黏膜经历慢性萎缩性胃炎、肠化生、异型增生直至胃癌发生的多阶段渐进性过程。其中肠化生是胃癌尤其是肠型胃癌重要的癌前病变。有研究证实,在肠化生及胃癌的发生过程中,性别决定区Y框蛋白2(SRY related HMG box-2,...胃癌的发生是由正常胃黏膜经历慢性萎缩性胃炎、肠化生、异型增生直至胃癌发生的多阶段渐进性过程。其中肠化生是胃癌尤其是肠型胃癌重要的癌前病变。有研究证实,在肠化生及胃癌的发生过程中,性别决定区Y框蛋白2(SRY related HMG box-2,SOX2)、尾侧型同源转录因子2(caudal related homeobox transcription factor-2,CDX2)和肝细胞核因子(hepatocyte nuclear factor,HNF)4α均有参与,而且3个分子间存在明显相关性。因此,本文对目前SOX2、CDX2和HNF4α与胃癌的相关研究进展作一综述。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
The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects o...The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics,whereas metabolism of cholesterol,bile acids(BAs),lipids,and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism.As a wellestablished master regulator of liver development and function,hepatocyte nuclear factor 4 alpha(HNF4α)plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics,metabolic wastes,and nutrients.The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone,glucocorticoids,thyroid hormone,insulin,transforming growth factor-β,estrogen,and cytokines.HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver.There have been a few reviews on the regulation of drug metabolism,lipid metabolism,cell proliferation,and inflammation by HNF4α.However,the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered.Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α,and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.展开更多
文摘胃癌的发生是由正常胃黏膜经历慢性萎缩性胃炎、肠化生、异型增生直至胃癌发生的多阶段渐进性过程。其中肠化生是胃癌尤其是肠型胃癌重要的癌前病变。有研究证实,在肠化生及胃癌的发生过程中,性别决定区Y框蛋白2(SRY related HMG box-2,SOX2)、尾侧型同源转录因子2(caudal related homeobox transcription factor-2,CDX2)和肝细胞核因子(hepatocyte nuclear factor,HNF)4α均有参与,而且3个分子间存在明显相关性。因此,本文对目前SOX2、CDX2和HNF4α与胃癌的相关研究进展作一综述。
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.
基金partly supported by U.S. National Institute of Health (NIH) Grant ES019487
文摘The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis.Metabolism of xenobiotics,such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics,whereas metabolism of cholesterol,bile acids(BAs),lipids,and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism.As a wellestablished master regulator of liver development and function,hepatocyte nuclear factor 4 alpha(HNF4α)plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics,metabolic wastes,and nutrients.The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone,glucocorticoids,thyroid hormone,insulin,transforming growth factor-β,estrogen,and cytokines.HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver.There have been a few reviews on the regulation of drug metabolism,lipid metabolism,cell proliferation,and inflammation by HNF4α.However,the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered.Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α,and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.
