Ovarian hyperandrogenism is one of the characteristics of polycystic ovary syndrome(PCOS)and androgen receptor(AR)in ovarian granulosa cells(GCs)functions as an important element to the accumulation of androgens.This ...Ovarian hyperandrogenism is one of the characteristics of polycystic ovary syndrome(PCOS)and androgen receptor(AR)in ovarian granulosa cells(GCs)functions as an important element to the accumulation of androgens.This study verified the existence of alternative splicing variant of AR(AR-SVs)in the GCs of PCOS patients and found that the function of AR decreased significantly in the presence of AR-SVs.And compared to the normal individuals,the expression of Serine/arginine-rich splicing factor 2(SRSF2)was higher and the expression of SRSF3 was lower in the GCs of patients with AR-SVs.More importantly,we found that the expression of SRSF2 was inhibited and that the expression of AR was decreased after the successful upregulation of miRNA-183,and testostrone(T)concentrations in the culture medium were increased.The results also showed that the expression of SRSF3 decreased when miRNA-124 was successfully upregulated,while the expression of AR significantly increased;however,the function of AR was also inhibited when T concentration in the culture medium was increased.This study has proved that SRSFs are regulated by corresponding miRNAs,and the altered expression of SRSFs interferenced the alternative splicing process of AR and ultimately decreased the function of AR,leading to the accumulation of androgens in the ovary.展开更多
Objectives:NOD-like receptor family pyrin domain-containing(NLRP)1-mediated pyroptosis plays a key role in the pathogenesis of cerebral ischemia-reperfusion injury(CIRI).C-Myc is reported to play a major role in CIRI....Objectives:NOD-like receptor family pyrin domain-containing(NLRP)1-mediated pyroptosis plays a key role in the pathogenesis of cerebral ischemia-reperfusion injury(CIRI).C-Myc is reported to play a major role in CIRI.However,the mechanism remains unclear.This study aimed to investigate whether c-Myc affects CIRI by regulating Serine/Arginine-rich Splicing Factor 1(SRSF1)/NLRP1-mediated pyroptosis.Methods:Oxygen-glucose deprivation/reperfusion(OGD/R)induced neuroblastoma cells for the establishment of an in vitro CIRI model.The levels of c-Myc and SRSF1,cell viability,the expression of pyroptosis-related factors,and the interaction between SRSF1 and NLRP1 were evaluated.Results:The expression of c-Myc and SRSF1 was decreased in OGD/R-induced neuroblastoma cells.c-Myc overexpression increased c-Myc and SRSF1 expression and cell viability in OGD/Rinduced neuroblastoma cells while inhibiting NLRP1,Caspase1,apoptosis-associated speck-like protein containing a CARD(ASC),interleukin-1beta(IL-1β),IL-18,and lactate dehydrogenase levels and pyroptosis.C-Myc was positively correlated with SRSF1.SRSF1 low expression reversed the effects of c-Myc on the above indicators in OGD/Rinduced neuroblastoma cells.Mechanically,SRSF1 interacted with NLRP1.SRSF1 was negatively correlated with NLRP1.The NLRP1 activator muramyl dipeptide(MDP)reversed the SRSF1 effect on OGD/R-induced neuroblastoma cells.Conclusion:Our results indicated that c-Myc reduced OGD/R-induced neuroblastoma cell pyroptosis by inhibiting NLRP1 activation by positive feedback SRSF1 signal.Our findings suggested that the c-Myc/SRSF1 axis might be a new strategy for treating CIRI in the clinic.展开更多
人类基因中约有94％发生选择性剪接，使同一前体 m R‐NA分子产生不同基因型，编码不同蛋白质，极大增加了基因表达复杂程度和蛋白质多样性［1］。不同组织出现疾病时显示特定模式剪接变异体，这些剪接模式依赖于剪接因子在细胞核中的...人类基因中约有94％发生选择性剪接，使同一前体 m R‐NA分子产生不同基因型，编码不同蛋白质，极大增加了基因表达复杂程度和蛋白质多样性［1］。不同组织出现疾病时显示特定模式剪接变异体，这些剪接模式依赖于剪接因子在细胞核中的相对表达，包括表达量或翻译后修饰［2］。富含丝氨酸／精氨酸剪接因子1（SRSF1），是1个典型富含丝氨酸／精氨酸SR蛋白家族成员，参与基因组成性剪接和选择性剪接［3］。SRSF1通过调节基因选择性剪接参与肿瘤形成发展。展开更多
[目的]探讨SRSF2/tGLI1轴调控Her2阳性乳腺癌侵袭的潜在机制。[方法]在TCGA和GEO数据集(GSE12276、GSE2034、GSE2603、GSE5327、GSE14020)中,分析SRSF2在正常组织和HER2阳性乳腺癌组织中的表达水平以及对无远处转移生存的影响。过表达...[目的]探讨SRSF2/tGLI1轴调控Her2阳性乳腺癌侵袭的潜在机制。[方法]在TCGA和GEO数据集(GSE12276、GSE2034、GSE2603、GSE5327、GSE14020)中,分析SRSF2在正常组织和HER2阳性乳腺癌组织中的表达水平以及对无远处转移生存的影响。过表达或敲低SRSF2或GLI1后,检测HER2阳性乳腺癌细胞SKBR-3、HCC1419、AU-565的侵袭细胞数。敲低SRSF2后分析GLI1的剪接形式,并且过表达GLI1不同剪接形式(fGLI1和tGLI1)后检测HER2阳性乳腺癌细胞的侵袭细胞数。[结果]在TCGA和GEO数据集中,与正常组织相比,HER2阳性乳腺癌组织中SRSF2的mRNA表达上升5倍(1.00±0.05 vs 5.74±0.37,P<0.05)。同时,SRSF2高表达的HER2阳性乳腺癌患者具有更短的无远处转移生存(P<0.05)。过表达SRSF2后,HER2阳性乳腺癌细胞的侵袭细胞数上升2倍(152.88±25.15个vs 376.47±32.31个,P<0.05)。敲低SRSF2后,HER2阳性乳腺癌细胞中fGLI1的mRNA表达上升,tGLI1的mRNA表达下降。过表达tGLI1后,HER2阳性乳腺癌细胞的侵袭细胞数上升3倍(147.43±21.99个vs 397.42±34.03个,P<0.05)。[结论]SRSF2通过选择性剪接将GLI1剪接成tGLI1的形式后,可促进HER2阳性乳腺癌的侵袭能力(152.88±25.15 vs 376.47±32.31,P<0.05)。展开更多
文摘Ovarian hyperandrogenism is one of the characteristics of polycystic ovary syndrome(PCOS)and androgen receptor(AR)in ovarian granulosa cells(GCs)functions as an important element to the accumulation of androgens.This study verified the existence of alternative splicing variant of AR(AR-SVs)in the GCs of PCOS patients and found that the function of AR decreased significantly in the presence of AR-SVs.And compared to the normal individuals,the expression of Serine/arginine-rich splicing factor 2(SRSF2)was higher and the expression of SRSF3 was lower in the GCs of patients with AR-SVs.More importantly,we found that the expression of SRSF2 was inhibited and that the expression of AR was decreased after the successful upregulation of miRNA-183,and testostrone(T)concentrations in the culture medium were increased.The results also showed that the expression of SRSF3 decreased when miRNA-124 was successfully upregulated,while the expression of AR significantly increased;however,the function of AR was also inhibited when T concentration in the culture medium was increased.This study has proved that SRSFs are regulated by corresponding miRNAs,and the altered expression of SRSFs interferenced the alternative splicing process of AR and ultimately decreased the function of AR,leading to the accumulation of androgens in the ovary.
基金supported by a fund from the Hainan Provincial Natural Science Foundation of China(No.821MS156).
文摘Objectives:NOD-like receptor family pyrin domain-containing(NLRP)1-mediated pyroptosis plays a key role in the pathogenesis of cerebral ischemia-reperfusion injury(CIRI).C-Myc is reported to play a major role in CIRI.However,the mechanism remains unclear.This study aimed to investigate whether c-Myc affects CIRI by regulating Serine/Arginine-rich Splicing Factor 1(SRSF1)/NLRP1-mediated pyroptosis.Methods:Oxygen-glucose deprivation/reperfusion(OGD/R)induced neuroblastoma cells for the establishment of an in vitro CIRI model.The levels of c-Myc and SRSF1,cell viability,the expression of pyroptosis-related factors,and the interaction between SRSF1 and NLRP1 were evaluated.Results:The expression of c-Myc and SRSF1 was decreased in OGD/R-induced neuroblastoma cells.c-Myc overexpression increased c-Myc and SRSF1 expression and cell viability in OGD/Rinduced neuroblastoma cells while inhibiting NLRP1,Caspase1,apoptosis-associated speck-like protein containing a CARD(ASC),interleukin-1beta(IL-1β),IL-18,and lactate dehydrogenase levels and pyroptosis.C-Myc was positively correlated with SRSF1.SRSF1 low expression reversed the effects of c-Myc on the above indicators in OGD/Rinduced neuroblastoma cells.Mechanically,SRSF1 interacted with NLRP1.SRSF1 was negatively correlated with NLRP1.The NLRP1 activator muramyl dipeptide(MDP)reversed the SRSF1 effect on OGD/R-induced neuroblastoma cells.Conclusion:Our results indicated that c-Myc reduced OGD/R-induced neuroblastoma cell pyroptosis by inhibiting NLRP1 activation by positive feedback SRSF1 signal.Our findings suggested that the c-Myc/SRSF1 axis might be a new strategy for treating CIRI in the clinic.
文摘人类基因中约有94％发生选择性剪接，使同一前体 m R‐NA分子产生不同基因型，编码不同蛋白质，极大增加了基因表达复杂程度和蛋白质多样性［1］。不同组织出现疾病时显示特定模式剪接变异体，这些剪接模式依赖于剪接因子在细胞核中的相对表达，包括表达量或翻译后修饰［2］。富含丝氨酸／精氨酸剪接因子1（SRSF1），是1个典型富含丝氨酸／精氨酸SR蛋白家族成员，参与基因组成性剪接和选择性剪接［3］。SRSF1通过调节基因选择性剪接参与肿瘤形成发展。
文摘[目的]探讨SRSF2/tGLI1轴调控Her2阳性乳腺癌侵袭的潜在机制。[方法]在TCGA和GEO数据集(GSE12276、GSE2034、GSE2603、GSE5327、GSE14020)中,分析SRSF2在正常组织和HER2阳性乳腺癌组织中的表达水平以及对无远处转移生存的影响。过表达或敲低SRSF2或GLI1后,检测HER2阳性乳腺癌细胞SKBR-3、HCC1419、AU-565的侵袭细胞数。敲低SRSF2后分析GLI1的剪接形式,并且过表达GLI1不同剪接形式(fGLI1和tGLI1)后检测HER2阳性乳腺癌细胞的侵袭细胞数。[结果]在TCGA和GEO数据集中,与正常组织相比,HER2阳性乳腺癌组织中SRSF2的mRNA表达上升5倍(1.00±0.05 vs 5.74±0.37,P<0.05)。同时,SRSF2高表达的HER2阳性乳腺癌患者具有更短的无远处转移生存(P<0.05)。过表达SRSF2后,HER2阳性乳腺癌细胞的侵袭细胞数上升2倍(152.88±25.15个vs 376.47±32.31个,P<0.05)。敲低SRSF2后,HER2阳性乳腺癌细胞中fGLI1的mRNA表达上升,tGLI1的mRNA表达下降。过表达tGLI1后,HER2阳性乳腺癌细胞的侵袭细胞数上升3倍(147.43±21.99个vs 397.42±34.03个,P<0.05)。[结论]SRSF2通过选择性剪接将GLI1剪接成tGLI1的形式后,可促进HER2阳性乳腺癌的侵袭能力(152.88±25.15 vs 376.47±32.31,P<0.05)。
