Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy.The transcription factor gene heart and neural crest derivatives expressed1(Hand1)...Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy.The transcription factor gene heart and neural crest derivatives expressed1(Hand1)promotes differentiation of mouse trophoblast giant cells.However,the role of HAND1 in human trophoblasts remains unknown.Here,we report that HAND1 inhibits human trophoblastic progesterone(P4)and estradiol(E2)from cholesterol through downregulation of the expression of steroidogenic enzymes,including aromatase,P450 cholesterol side-chain cleavage enzyme(P450 scc),and 3β-hydroxysteroid dehydrogenase type 1(3β-HSD1).Mechanically,although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter,it restrains transcription of P450 scc by upregulation of the methylation status of P450 scc gene promoter through its binding to ALKBH1,a demethylase.Unlike aromatase and P450 scc,HAND1 decreases 3β-HSD1 m RNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein Hu R.Finally,HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2.Thus,our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts,which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.展开更多
BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found t...BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.展开更多
目的:观察亮氨酸拉链EF-hand结构域跨膜蛋白1(leucine zipper/EF-hand-containing transmembrane protein 1,LETM1)在结肠癌中的表达情况,探讨LETM1蛋白是否能够成为判断结肠癌患者预后的新的生物学指标.方法:利用免疫组织化学法检测73...目的:观察亮氨酸拉链EF-hand结构域跨膜蛋白1(leucine zipper/EF-hand-containing transmembrane protein 1,LETM1)在结肠癌中的表达情况,探讨LETM1蛋白是否能够成为判断结肠癌患者预后的新的生物学指标.方法:利用免疫组织化学法检测73例结肠癌患者组织中LETM1蛋白的表达水平和蛋白激酶B(protein kinase B,PKB)/Akt的丝氨酸473(Ser473)、苏氨酸308(Thr308)两个磷酸化位点及葡萄糖合成激酶3β(glycogen synthase k i n a s e 3β,G S K3β)的磷酸化水平,并根据LETM1蛋白表达水平进行高表达和低表达分组;采用Kaplan-Meier法分析各组无疾病生存期;采用χ2检验进行组间单因素分析.结果:在结肠癌患者中LETM1蛋白高表达率为54.8%,LETM1蛋白在结肠癌浸润深度、分化及淋巴结转移中低表达和高表达率分别为27.3%/72.7%、38.3%/61.7%和22.7%/77.3%,其差异均有统计学意义(P<0.05),而与年龄、性别、肿瘤大小未见统计学意义(P>0.05).LETM1蛋白在结肠癌组织中可以激活磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase,PI-3K)/A k t信号传导通路.L ETM1高表达患者无疾病生存期显著低于LETM1低表达患者(P<0.05).结论:LETM1蛋白在结肠癌中高表达,可能参与结肠癌的发生、发展与复发.LETM1蛋白可以作为预测结肠癌患者预后的新的生物学指标.展开更多
目的通过Meta分析评估血液中lncRNA HAND2反义RNA1(HAND2-AS1)的表达水平对多种肿瘤的临床诊断价值。方法由两名评价员利用计算机检索PubMed、Embase、SinoMed和万方等数据库,检索时限为1980年1月1日至2020年9月30日,收集国内外公开发...目的通过Meta分析评估血液中lncRNA HAND2反义RNA1(HAND2-AS1)的表达水平对多种肿瘤的临床诊断价值。方法由两名评价员利用计算机检索PubMed、Embase、SinoMed和万方等数据库,检索时限为1980年1月1日至2020年9月30日,收集国内外公开发表有关HAND2-AS1表达水平与肿瘤癌症相关的所有文献,采用STATA 14.0软件对数据进行Meta分析。结果严格按照纳入和排除标准,筛选出6篇文献进行Meta分析,包括317名肿瘤患者和227名健康对照者。连续型变量所合并的效应量为标准化均数差(Standardized mean difference,SMD),具体为[SMD=-1.61,95%CI(-1.80,-1.41),P<0.00001]。对于HAND2-AS1的诊断价值,汇总敏感度、特异度分别为0.87和0.82,诊断比值比(Diagnostic Odds Ratio,DOR)为32,综合受试者工作特征曲线的曲线下面积(Aarea under curve,AUC)为0.91。结论血液中HAND2-AS1的检测在多种肿瘤的诊断中具有较高的敏感度和特异度,对区分患者和健康个体具有较高的临床诊断价值。展开更多
Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly ...Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.展开更多
基金supported by Natural Science Foundation of Zhejiang Province (LY17H160023 to H.Z.)National Basic Research Program of China (973 Program, 2018YFC1004404 to X.W.)+1 种基金Starting Research Foundation from The Children’s Hospital,Zhejiang University School of Medicine (481)National Natural Science Foundation of China (31801207 to C.T.)
文摘Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy.The transcription factor gene heart and neural crest derivatives expressed1(Hand1)promotes differentiation of mouse trophoblast giant cells.However,the role of HAND1 in human trophoblasts remains unknown.Here,we report that HAND1 inhibits human trophoblastic progesterone(P4)and estradiol(E2)from cholesterol through downregulation of the expression of steroidogenic enzymes,including aromatase,P450 cholesterol side-chain cleavage enzyme(P450 scc),and 3β-hydroxysteroid dehydrogenase type 1(3β-HSD1).Mechanically,although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter,it restrains transcription of P450 scc by upregulation of the methylation status of P450 scc gene promoter through its binding to ALKBH1,a demethylase.Unlike aromatase and P450 scc,HAND1 decreases 3β-HSD1 m RNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein Hu R.Finally,HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2.Thus,our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts,which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.
文摘BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.
文摘目的:观察亮氨酸拉链EF-hand结构域跨膜蛋白1(leucine zipper/EF-hand-containing transmembrane protein 1,LETM1)在结肠癌中的表达情况,探讨LETM1蛋白是否能够成为判断结肠癌患者预后的新的生物学指标.方法:利用免疫组织化学法检测73例结肠癌患者组织中LETM1蛋白的表达水平和蛋白激酶B(protein kinase B,PKB)/Akt的丝氨酸473(Ser473)、苏氨酸308(Thr308)两个磷酸化位点及葡萄糖合成激酶3β(glycogen synthase k i n a s e 3β,G S K3β)的磷酸化水平,并根据LETM1蛋白表达水平进行高表达和低表达分组;采用Kaplan-Meier法分析各组无疾病生存期;采用χ2检验进行组间单因素分析.结果:在结肠癌患者中LETM1蛋白高表达率为54.8%,LETM1蛋白在结肠癌浸润深度、分化及淋巴结转移中低表达和高表达率分别为27.3%/72.7%、38.3%/61.7%和22.7%/77.3%,其差异均有统计学意义(P<0.05),而与年龄、性别、肿瘤大小未见统计学意义(P>0.05).LETM1蛋白在结肠癌组织中可以激活磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase,PI-3K)/A k t信号传导通路.L ETM1高表达患者无疾病生存期显著低于LETM1低表达患者(P<0.05).结论:LETM1蛋白在结肠癌中高表达,可能参与结肠癌的发生、发展与复发.LETM1蛋白可以作为预测结肠癌患者预后的新的生物学指标.
文摘目的通过Meta分析评估血液中lncRNA HAND2反义RNA1(HAND2-AS1)的表达水平对多种肿瘤的临床诊断价值。方法由两名评价员利用计算机检索PubMed、Embase、SinoMed和万方等数据库,检索时限为1980年1月1日至2020年9月30日,收集国内外公开发表有关HAND2-AS1表达水平与肿瘤癌症相关的所有文献,采用STATA 14.0软件对数据进行Meta分析。结果严格按照纳入和排除标准,筛选出6篇文献进行Meta分析,包括317名肿瘤患者和227名健康对照者。连续型变量所合并的效应量为标准化均数差(Standardized mean difference,SMD),具体为[SMD=-1.61,95%CI(-1.80,-1.41),P<0.00001]。对于HAND2-AS1的诊断价值,汇总敏感度、特异度分别为0.87和0.82,诊断比值比(Diagnostic Odds Ratio,DOR)为32,综合受试者工作特征曲线的曲线下面积(Aarea under curve,AUC)为0.91。结论血液中HAND2-AS1的检测在多种肿瘤的诊断中具有较高的敏感度和特异度,对区分患者和健康个体具有较高的临床诊断价值。
基金supported by Grants from the National Natural Science Foundation of China (81571987)
文摘Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.
