Cardiac fibrosis is characterized by an elevated amount of extracellular matrix(ECM)within the heart.However,the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction...Cardiac fibrosis is characterized by an elevated amount of extracellular matrix(ECM)within the heart.However,the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction.Circular RNAs(circRNAs)are emerging as important regulators of cardiac fibrosis.Here,we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism.Functionally,circ-CELF1 was involved in enhancing fibrosis-related markers'expression and promoting the proliferation of cardiac fibroblasts(CFs),thereby exacerbating cardiac fibrosis.Mechanistically,circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3,leading to an elevation of BRPF3 protein levels.Additionally,BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene.Thus,the transcription of Celf1 was dramatically activated,thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis.Moreover,Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing,thereby establishing a feedback loop for circ-CELF1 production.Consequently,a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established,suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.展开更多
目的探索酮还原酶家族1成员C3(aldo-keto reductase family 1 member C3,AKR1C3)对乳腺癌恶性细胞生物学行为的干预作用及对程序性细胞死亡蛋白/程序性死亡-配体1(programmed cell death protein1/programmed death-ligand1,PD-1/PD-L)...目的探索酮还原酶家族1成员C3(aldo-keto reductase family 1 member C3,AKR1C3)对乳腺癌恶性细胞生物学行为的干预作用及对程序性细胞死亡蛋白/程序性死亡-配体1(programmed cell death protein1/programmed death-ligand1,PD-1/PD-L)通路的影响。方法把MCF-7人乳腺癌细胞中NC组和AKR1C3组分别转染空质粒和AKR1C3质粒,采用MTT法检测转染后24 h、48 h、72 h细胞活力;采用流式细胞技术测定各组细胞的存活率以及早期、晚期凋亡比例;通过Transwell实验对各组细胞的迁移和侵袭能力进行检测;通过Western blot检测各组细胞PD-1、PD-L1、蛋白激酶B(protein kinase b,AKT)蛋白表达水平。使用C57BL/6小鼠构建荷瘤模型,将采用人乳腺癌MCF-7细胞转染NC质粒和AKR1C3质粒进行细胞荷瘤,每3 d测量瘤体积,持续21 d,绘制两组小鼠肿瘤生长曲线,并于实验终点测量肿瘤质量。结果相较于NC组,AKR1C3组细胞活力降低(P<0.05),并且具有时间依赖效应(P<0.05),迁移和侵袭能力降低(P<0.05),早期凋亡和晚期凋亡比例升高(P<0.05),PD-1、PD-L1、AKT蛋白表达水平降低(P<0.05)。动物实验表明,AKR1C3组小鼠肿瘤体积降低,肿瘤质量下降(P<0.05)。结论AKR1C3可以抑制人乳腺癌细胞恶性生物学行为,抑制PD-1/PDL1信号通路蛋白表达。展开更多
基金supported by research grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project(Nos.2024ZD0521500 and 2024ZD0521501,China)the National Natural Science Foundation of China(82270246,82070240,82470280 and 82300493)+1 种基金the Natural Science Foundation of Heilongjiang Province of China(JJ2024LH2446)China Postdoctoral Science Foundation(2023MD734169,China).
文摘Cardiac fibrosis is characterized by an elevated amount of extracellular matrix(ECM)within the heart.However,the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction.Circular RNAs(circRNAs)are emerging as important regulators of cardiac fibrosis.Here,we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism.Functionally,circ-CELF1 was involved in enhancing fibrosis-related markers'expression and promoting the proliferation of cardiac fibroblasts(CFs),thereby exacerbating cardiac fibrosis.Mechanistically,circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3,leading to an elevation of BRPF3 protein levels.Additionally,BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene.Thus,the transcription of Celf1 was dramatically activated,thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis.Moreover,Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing,thereby establishing a feedback loop for circ-CELF1 production.Consequently,a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established,suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.
