目的:探讨NR5A2 rs3790843基因多态性与女性胃癌患者临床病理特征及预后的关系。方法:检测211例女性胃癌患者石蜡组织DNA上rs3790843基因多态性。采用Kaplan-Meier法、Log-rank检验及Cox回归分析NR5A2 rs3790843基因多态性对女性胃癌患...目的:探讨NR5A2 rs3790843基因多态性与女性胃癌患者临床病理特征及预后的关系。方法:检测211例女性胃癌患者石蜡组织DNA上rs3790843基因多态性。采用Kaplan-Meier法、Log-rank检验及Cox回归分析NR5A2 rs3790843基因多态性对女性胃癌患者临床病理特征及预后的影响。结果:非贲门癌组较贲门癌组能显著降低死亡风险,而有淋巴转移、远处转移、TNM分期较晚的患者,其死亡风险明显提高。在共显性模型中(TT vs TC vs CC),携带TC基因型的患者相较与携带TT基因的患者,死亡风险明显降低(HR=0.616,95%CI 0.409~0.928),在显性基因模型中(TT v s TC/CC),携带TC/CC基因型的胃癌患者死亡风险相较携带T T基因型者,死亡风险明显降低(HR=0.619,95%CI 0.417~0.916,P=0.015)。而在隐性模型中(TT/TC vs CC),携带TT/TC基因型的患者与携带CC基因型的患者的生存无显著差异。分层分析发现:在年龄≤60岁、非贲门癌、肿瘤>5 cm、有淋巴结转移、无远处转移、弥漫性胃癌、分化程度差、无术后辅助化疗、T4组、临床分期III期的分组中,rs3790843基因多态性能显著降低死亡风险。多因素Cox回归分析结果表明:有无淋巴结转移、肿瘤部位、rs3790843(TT vs TC/CC)均可作为影响女性胃癌患者的独立预后因子。结论:NR5A2 rs3790843基因的T→C的突变能显著降低女性胃癌患者的死亡风险,是一个女性胃癌预后的保护性因素,可作为女性胃癌患者预后的独立预测指标。展开更多
Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary L...Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary LF epigenetically modulates the oxidative genes by histone modifications to ameliorate ileum inflammation of mice exposed to DON contaminated diet.As expected,we found in the morphology analysis that DON exposure increased ileum crypt depth(CD)and villus width(VW)but reduced villus height(VH)and VH:CD ratio compared to those of the vehicle group.Consistently,the elevated ROS and MDA,along with the decreased ATP,SOD,CAT,GSH,and complex I,III,V were observed in the DON-exposed mice ileum.In contrast,LF markedly ameliorated the impairments of morphological and biochemical indexes.Next,we conducted transcriptome analysis to explore the changed signaling pathways using the ileum RNA of the mice treated with DON or LF.Firstly,the cell cycle pathway genes were significantly downregulated in the DON-exposed mice,and LF improved the cell cycle profile.Again,gene ontology analysis showed that inflammation and oxidative stress were significantly activated by DON exposure,and these were recovered when the DON-exposed mice were supplemented with an LF diet.Consistent with these findings,the signaling pathways of the reduced oxidative phosphorylation and elevated TNFαwere also observed to be ameliorated by LF treatment.Importantly,histone modifications,including acetylation,methylation,and lactylation were suggested to be the vital players involved in the DON or LF treatment,in which LF significantly increased the loss of histone modifications on these genes.With a bioinformatics analysis and validation by qRT-PCR,the nuclear receptor NR5A2 was selected as a key master in the ileum of mice stimulated by DON.LF performed the benefit function on the NR5A2-mediated oxidative stress genes Ncoa4 and Prdx3 in the DON-exposed mice.Moreover,a ChIP-qPCR was used to verify that histone marks involving H3K9ac,H3K18ac,H3k27ac,H3K4me1,H3K9la,and H3K18la facilitated the epigenetic regulation of NR5A2-modulated actions.We conclude that dietary LF effectively ameliorated ileum lesions induced by DON in mice by modulating oxidative genes Ncoa4 and Prdx3 through histone modifications.展开更多
We have cloned the cDNA of human nuclear receptor nr5a2(hb1f) gene and obtained its whole genomic sequence previously. In this work we carried out in-depth bioinformatic analysis on the genomic sequence of nr5a2(hb1f)...We have cloned the cDNA of human nuclear receptor nr5a2(hb1f) gene and obtained its whole genomic sequence previously. In this work we carried out in-depth bioinformatic analysis on the genomic sequence of nr5a2(hb1f) gene. Sequence comparison and prediction algorithms implicated that there might be additional coding regions in the 210 kb genomic sequence besides known exons, especially in the two largest introns. Comparison of the structures of nr5a loci in different species revealed distinguishable conservation and apparent gene duplication during evolution. The remarkable conservation among promoters of zebrafish, mouse and human nr5a2 genes suggested that they would be regulated by the same transcription factors.展开更多
Cancer stem cells (CSCs) are largely responsible for the formation of tumor heterogeneity and tumor’s resistance to traditional treatments such as chemotherapy due to its self-renew capability and multi-lineage diffe...Cancer stem cells (CSCs) are largely responsible for the formation of tumor heterogeneity and tumor’s resistance to traditional treatments such as chemotherapy due to its self-renew capability and multi-lineage differentiation potential (1)However, it remains elusive how the CSCs maintain their stemness, thus restricting the development of therapeutic treatments specifically targeting the CSCs.展开更多
Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in ...Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.展开更多
文摘目的:探讨NR5A2 rs3790843基因多态性与女性胃癌患者临床病理特征及预后的关系。方法:检测211例女性胃癌患者石蜡组织DNA上rs3790843基因多态性。采用Kaplan-Meier法、Log-rank检验及Cox回归分析NR5A2 rs3790843基因多态性对女性胃癌患者临床病理特征及预后的影响。结果:非贲门癌组较贲门癌组能显著降低死亡风险,而有淋巴转移、远处转移、TNM分期较晚的患者,其死亡风险明显提高。在共显性模型中(TT vs TC vs CC),携带TC基因型的患者相较与携带TT基因的患者,死亡风险明显降低(HR=0.616,95%CI 0.409~0.928),在显性基因模型中(TT v s TC/CC),携带TC/CC基因型的胃癌患者死亡风险相较携带T T基因型者,死亡风险明显降低(HR=0.619,95%CI 0.417~0.916,P=0.015)。而在隐性模型中(TT/TC vs CC),携带TT/TC基因型的患者与携带CC基因型的患者的生存无显著差异。分层分析发现:在年龄≤60岁、非贲门癌、肿瘤>5 cm、有淋巴结转移、无远处转移、弥漫性胃癌、分化程度差、无术后辅助化疗、T4组、临床分期III期的分组中,rs3790843基因多态性能显著降低死亡风险。多因素Cox回归分析结果表明:有无淋巴结转移、肿瘤部位、rs3790843(TT vs TC/CC)均可作为影响女性胃癌患者的独立预后因子。结论:NR5A2 rs3790843基因的T→C的突变能显著降低女性胃癌患者的死亡风险,是一个女性胃癌预后的保护性因素,可作为女性胃癌患者预后的独立预测指标。
基金funded by Jiangsu Higher Education Key Natural Science Research Program(21 KJA230002)Yangzhou Hanjiang sci-tech project.Jiangsu Higher Education Key Natural Science Research Program,21 KJA230002,Dejun Ji,Yangzhou Hanjiang sci-tech project。
文摘Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary LF epigenetically modulates the oxidative genes by histone modifications to ameliorate ileum inflammation of mice exposed to DON contaminated diet.As expected,we found in the morphology analysis that DON exposure increased ileum crypt depth(CD)and villus width(VW)but reduced villus height(VH)and VH:CD ratio compared to those of the vehicle group.Consistently,the elevated ROS and MDA,along with the decreased ATP,SOD,CAT,GSH,and complex I,III,V were observed in the DON-exposed mice ileum.In contrast,LF markedly ameliorated the impairments of morphological and biochemical indexes.Next,we conducted transcriptome analysis to explore the changed signaling pathways using the ileum RNA of the mice treated with DON or LF.Firstly,the cell cycle pathway genes were significantly downregulated in the DON-exposed mice,and LF improved the cell cycle profile.Again,gene ontology analysis showed that inflammation and oxidative stress were significantly activated by DON exposure,and these were recovered when the DON-exposed mice were supplemented with an LF diet.Consistent with these findings,the signaling pathways of the reduced oxidative phosphorylation and elevated TNFαwere also observed to be ameliorated by LF treatment.Importantly,histone modifications,including acetylation,methylation,and lactylation were suggested to be the vital players involved in the DON or LF treatment,in which LF significantly increased the loss of histone modifications on these genes.With a bioinformatics analysis and validation by qRT-PCR,the nuclear receptor NR5A2 was selected as a key master in the ileum of mice stimulated by DON.LF performed the benefit function on the NR5A2-mediated oxidative stress genes Ncoa4 and Prdx3 in the DON-exposed mice.Moreover,a ChIP-qPCR was used to verify that histone marks involving H3K9ac,H3K18ac,H3k27ac,H3K4me1,H3K9la,and H3K18la facilitated the epigenetic regulation of NR5A2-modulated actions.We conclude that dietary LF effectively ameliorated ileum lesions induced by DON in mice by modulating oxidative genes Ncoa4 and Prdx3 through histone modifications.
基金This work was supported by the National Natural Science Foundation of China (Grant No. 39893320-4)the Chinese Human Genome Center at Shanghai (Grant No. CNCS-98-M-06)+1 种基金the Basic Research Program from the Ministry of Science Technology (Grant No. G19
文摘We have cloned the cDNA of human nuclear receptor nr5a2(hb1f) gene and obtained its whole genomic sequence previously. In this work we carried out in-depth bioinformatic analysis on the genomic sequence of nr5a2(hb1f) gene. Sequence comparison and prediction algorithms implicated that there might be additional coding regions in the 210 kb genomic sequence besides known exons, especially in the two largest introns. Comparison of the structures of nr5a loci in different species revealed distinguishable conservation and apparent gene duplication during evolution. The remarkable conservation among promoters of zebrafish, mouse and human nr5a2 genes suggested that they would be regulated by the same transcription factors.
基金supported by National Key Scientific Program of China (2016YFA0100502 to X.S.)the National Natural Science Foundation of China (81701765 to J.C.)Anhui Provincial Natural Science Foundation (1808085MH295 to J.C.)
文摘Cancer stem cells (CSCs) are largely responsible for the formation of tumor heterogeneity and tumor’s resistance to traditional treatments such as chemotherapy due to its self-renew capability and multi-lineage differentiation potential (1)However, it remains elusive how the CSCs maintain their stemness, thus restricting the development of therapeutic treatments specifically targeting the CSCs.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040000)the Industrial Innovation Team grant from Foshan Industrial Technology Research Institute,Chinese Academy of Sciences,the National Natural Science Foundation of China(32070163,81871297,and 81903142)China ATOMIC Energy Authority,Foshan High-level Hospital Construction DengFeng Plan,and Guangdong Province Biomedical Innovation Platform Construction Project Tumor Immunobiotherapy.
文摘Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.
