Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HN...Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.展开更多
Objective Accumulating evidence suggests that transmembrane 4 L6 family member 1(TM4SF1)is associated with the development of various cancers;yet comprehensive studies on TM4SF1 in cervical cancer are lacking.Therefor...Objective Accumulating evidence suggests that transmembrane 4 L6 family member 1(TM4SF1)is associated with the development of various cancers;yet comprehensive studies on TM4SF1 in cervical cancer are lacking.Therefore,we aimed to evaluate the prognostic value of TM4SF1 in cervical cancer,elucidate its potential oncogenic functions in this disease,and further explore its feasibility as a therapeutic target.Methods The expression profiles and clinical information of cervical cancer patients were obtained from The Cancer Genome Atlas(TCGA)database.The expression levels of TM4SF1 were compared between cervical cancer and normal cervical tissues using the Wilcoxon rank-sum test.Kaplan–Meier analysis was employed to assess the prognostic value of TM4SF1.Furthermore,functional enrichment analyses were performed to explore the associated signaling pathways and biological functions.The methylation status of TM4SF1 was analyzed using the UALCAN and MethSurv databases.In addition,in vitro experiments were conducted to preliminarily validate the role and mechanisms of TM4SF1 in cervical cancer.Results TM4SF1 was overexpressed in nearly all tumors,and its overexpression was associated with poor prognosis in cervical cancer.Moreover,the correlation between TM4SF1 expression and the expression of immune cell infiltration markers and immune checkpoint genes suggested that it had potential applications in cancer immunotherapy.Western blot analysis and immunohistochemistry revealed significantly elevated protein levels of TM4SF1 in cervical cancer tissues and cells.Further studies revealed that the knockdown of TM4SF1 significantly inhibited the migration,invasion,and epithelial-mesenchymal transition(EMT)of HeLa and SiHa cells,as well as promoted their apoptosis.Conclusion TM4SF1 may serve as a potential prognostic biomarker and therapeutic target for cervical cancer.展开更多
目的:探讨有4个跨膜区的L6超家族成员1(transmembrane 4Lsix family member 1,TM4SF1)基因在上皮性卵巢癌(卵巢癌)组织中的表达及其临床价值。方法:用RT-PCR法检测TM4SF1基因在36例卵巢癌、15例卵巢良性肿瘤、13例正常卵巢组织中的表达...目的:探讨有4个跨膜区的L6超家族成员1(transmembrane 4Lsix family member 1,TM4SF1)基因在上皮性卵巢癌(卵巢癌)组织中的表达及其临床价值。方法:用RT-PCR法检测TM4SF1基因在36例卵巢癌、15例卵巢良性肿瘤、13例正常卵巢组织中的表达。结果:TM4SF1基因在卵巢癌中表达为(0.173±0.054)、良性肿瘤为(0.134±0.015)、正常卵巢组织为(0.118±0.008)。癌组织中的表达水平高于卵巢良性肿瘤(P=0.031);癌组织中的表达水平高于正常卵巢组织(P=0.004);良性卵巢肿瘤组织中的表达水平高于正常卵巢组织(P=0.012);手术—病理分期为Ⅰ-Ⅱ期癌组织中的表达水平(0.124±0.02)低于Ⅲ期(0.164±0.024)(P<0.05);高分化癌组织中的表达水平为(0.091±0.052),中—低分化癌组织表达为(0.113±0.024)(P>0.05)。结论:TM4SF1基因的表达与卵巢癌相关,可能在卵巢癌的发生、发展过程中起一定作用。展开更多
文摘Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
基金the Natural Science Fund of Hubei Province(No.2022CFC019 and No.2021CFB430).
文摘Objective Accumulating evidence suggests that transmembrane 4 L6 family member 1(TM4SF1)is associated with the development of various cancers;yet comprehensive studies on TM4SF1 in cervical cancer are lacking.Therefore,we aimed to evaluate the prognostic value of TM4SF1 in cervical cancer,elucidate its potential oncogenic functions in this disease,and further explore its feasibility as a therapeutic target.Methods The expression profiles and clinical information of cervical cancer patients were obtained from The Cancer Genome Atlas(TCGA)database.The expression levels of TM4SF1 were compared between cervical cancer and normal cervical tissues using the Wilcoxon rank-sum test.Kaplan–Meier analysis was employed to assess the prognostic value of TM4SF1.Furthermore,functional enrichment analyses were performed to explore the associated signaling pathways and biological functions.The methylation status of TM4SF1 was analyzed using the UALCAN and MethSurv databases.In addition,in vitro experiments were conducted to preliminarily validate the role and mechanisms of TM4SF1 in cervical cancer.Results TM4SF1 was overexpressed in nearly all tumors,and its overexpression was associated with poor prognosis in cervical cancer.Moreover,the correlation between TM4SF1 expression and the expression of immune cell infiltration markers and immune checkpoint genes suggested that it had potential applications in cancer immunotherapy.Western blot analysis and immunohistochemistry revealed significantly elevated protein levels of TM4SF1 in cervical cancer tissues and cells.Further studies revealed that the knockdown of TM4SF1 significantly inhibited the migration,invasion,and epithelial-mesenchymal transition(EMT)of HeLa and SiHa cells,as well as promoted their apoptosis.Conclusion TM4SF1 may serve as a potential prognostic biomarker and therapeutic target for cervical cancer.
文摘目的:探讨有4个跨膜区的L6超家族成员1(transmembrane 4Lsix family member 1,TM4SF1)基因在上皮性卵巢癌(卵巢癌)组织中的表达及其临床价值。方法:用RT-PCR法检测TM4SF1基因在36例卵巢癌、15例卵巢良性肿瘤、13例正常卵巢组织中的表达。结果:TM4SF1基因在卵巢癌中表达为(0.173±0.054)、良性肿瘤为(0.134±0.015)、正常卵巢组织为(0.118±0.008)。癌组织中的表达水平高于卵巢良性肿瘤(P=0.031);癌组织中的表达水平高于正常卵巢组织(P=0.004);良性卵巢肿瘤组织中的表达水平高于正常卵巢组织(P=0.012);手术—病理分期为Ⅰ-Ⅱ期癌组织中的表达水平(0.124±0.02)低于Ⅲ期(0.164±0.024)(P<0.05);高分化癌组织中的表达水平为(0.091±0.052),中—低分化癌组织表达为(0.113±0.024)(P>0.05)。结论:TM4SF1基因的表达与卵巢癌相关,可能在卵巢癌的发生、发展过程中起一定作用。
