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
Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the mole...Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.展开更多
Background:Lymph node metastasis is a significant indicator of recurrence and mortality in thyroid carcinoma and often guides treatment decisions.However,the characteristics and specific mechanisms of various cancer c...Background:Lymph node metastasis is a significant indicator of recurrence and mortality in thyroid carcinoma and often guides treatment decisions.However,the characteristics and specific mechanisms of various cancer cells that metastasize to lymph nodes are not clear.This study aims to characterize the cellular heterogeneity and transcriptomic dynamics of thyroid cancer.We further seek to elucidate the role of the key transcription factor FOXA2 in orchestrating a pro-metastatic and immunosuppressive program,specifically its regulation of T-cell activity and apoptosis.Our ultimate goal is to identify potential therapeutic strategies for thyroid cancer with lymph node metastasis.Methods:Using single-cell RNA-seq analyses,we investigated the dynamic of cellular heterogeneity transcriptome regulation and microenvironmental factors in 15,591 single cells from paired samples of primary and lymph node-metastasized tumors.The function of key factor was further investigated using data from public database and in vitro experiments.Results:We found that among all the six subclusters identified,the cancer cells(cluster 3)with higher tumor different ability(tumor different score)evolved into metastatic clusters infiltrating into lymph nodes.We also showed that the immune response-activating cell surface receptor signaling pathway is enriched in malignant cells of the metastatic lymph node.The interactions between T cells and other cells were weakened,and CCLs-mediated signals out/income T-cells are more likely to affect the in-teractions.Tumor-intrinsic forkhead box A2(FOXA2)orchestrated the thyroid cancer cell immunologic/metastatic signature and its expression is related to prognosis.FOXA2 knockdown promoted thyroid cancer cell migration,proliferation,and T-cell apoptosis.Moreover,its expression significantly influenced T-cell activity by the CCL2/LCN2-mediated signal pathway.Conclusions:These findings reveal that FOXA2 regulates cancer cell immunity by influencing T-cell apoptosis in thyroid cancer.Our results provide a potential pharmacological strategy for immune therapy in thyroid cancer with lymph node metastasis.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supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),funded by the Ministry of Education(RS-2023-00248378 and NRF-2020R1A6A1A03043708).
文摘Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.
基金supported by grants Shaanxi Provincial Key R&D Program(Grant 2023-YBSF-388)Innovation Fund Project of Tangdu Hospital(Grant 2019JSYJ014)。
文摘Background:Lymph node metastasis is a significant indicator of recurrence and mortality in thyroid carcinoma and often guides treatment decisions.However,the characteristics and specific mechanisms of various cancer cells that metastasize to lymph nodes are not clear.This study aims to characterize the cellular heterogeneity and transcriptomic dynamics of thyroid cancer.We further seek to elucidate the role of the key transcription factor FOXA2 in orchestrating a pro-metastatic and immunosuppressive program,specifically its regulation of T-cell activity and apoptosis.Our ultimate goal is to identify potential therapeutic strategies for thyroid cancer with lymph node metastasis.Methods:Using single-cell RNA-seq analyses,we investigated the dynamic of cellular heterogeneity transcriptome regulation and microenvironmental factors in 15,591 single cells from paired samples of primary and lymph node-metastasized tumors.The function of key factor was further investigated using data from public database and in vitro experiments.Results:We found that among all the six subclusters identified,the cancer cells(cluster 3)with higher tumor different ability(tumor different score)evolved into metastatic clusters infiltrating into lymph nodes.We also showed that the immune response-activating cell surface receptor signaling pathway is enriched in malignant cells of the metastatic lymph node.The interactions between T cells and other cells were weakened,and CCLs-mediated signals out/income T-cells are more likely to affect the in-teractions.Tumor-intrinsic forkhead box A2(FOXA2)orchestrated the thyroid cancer cell immunologic/metastatic signature and its expression is related to prognosis.FOXA2 knockdown promoted thyroid cancer cell migration,proliferation,and T-cell apoptosis.Moreover,its expression significantly influenced T-cell activity by the CCL2/LCN2-mediated signal pathway.Conclusions:These findings reveal that FOXA2 regulates cancer cell immunity by influencing T-cell apoptosis in thyroid cancer.Our results provide a potential pharmacological strategy for immune therapy in thyroid cancer with lymph node metastasis.
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.
