In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by perma- nent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal...In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by perma- nent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Miiller glial cells. Following injury, zebrafish Miiller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Mtiller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from ze- brafish and mammalian Mtiller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Mtiller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases.展开更多
目的:探讨ONECUT2(one cut homeobox 2,OC-2)基因在人胃癌组织中的表达水平及其临床意义。方法:基于生物信息学技术全面检索Oncomine、GEPIA、CCLE、EBI数据库,分析OC-2在胃癌和其他种类肿瘤中的表达水平,用Kmplot数据库验证其表达水平...目的:探讨ONECUT2(one cut homeobox 2,OC-2)基因在人胃癌组织中的表达水平及其临床意义。方法:基于生物信息学技术全面检索Oncomine、GEPIA、CCLE、EBI数据库,分析OC-2在胃癌和其他种类肿瘤中的表达水平,用Kmplot数据库验证其表达水平与胃癌患者预后的关系,用STRING数据库构建蛋白互作网络(protein protein interaction network,PPI network),分析与胃癌相关的OC-2共表达基因。结果:在OC-2差异表达的不同种类肿瘤中,其表达水平一般上调。在胃癌组织和细胞中OC-2表达水平均显著升高(均P<0.05),且可能与组织分型和肿瘤分期无关(均P>0.05)。OC-2表达水平与胃癌患者的预后有关,OC-2低表达组胃癌患者的中位总生存期和中位无病生存期均显著高于高表达组(40.0 vs 26.5个月,26.2 vs 16.1个月;均P<0.01)。筛查获得了15个OC-2的共表达基因;构建的PPI网络预测了30个功能蛋白与OC-2蛋白相互作用,其中有11个蛋白基因也与胃癌的发生发展有关,Pearson相关分析后得出4个与OC-2密切正相关的蛋白基因:PDX1(R=0.49)、CREB1(R=0.31)、MAPK1(R=0.26)、CTSS(R=0.25)。结论:OC-2在胃癌发生发展及侵袭转移过程中可能起重要的作用,有望成为胃癌诊治和判断预后的重要指标和新的筛查靶点。展开更多
The retina and its development： The retina is an essential part of the visual system. A myriad of eye diseases are characterized by retinal degeneration, caused by either genetic or environmental factors. This unders...The retina and its development： The retina is an essential part of the visual system. A myriad of eye diseases are characterized by retinal degeneration, caused by either genetic or environmental factors. This underscores the importance of studying the genetic and molecular mechanisms that regulate the generation and maintenance of neurons in the mammalian retina. Our recent studies demonstrate that two related transcription factors Onecutl （Ocl） and Onecut2 （0c2） regulate multiple cell fates in the mouse retina, and their absence results in progressive retinal neurodegeneration （Wu et al., 2012, 2013; Sapkota et al., 2014）.展开更多
目的:探讨miR-9-5p在乳腺癌恶性生物学行为中发挥的作用及其可能的调控机制。方法:利用OncomiR在线数据库分析miR-9-5p在乳腺癌组织与正常乳腺组织中表达的差异,qPCR检测乳腺癌细胞系与正常乳腺细胞中miR-9-5p表达水平。基于靶基因预测...目的:探讨miR-9-5p在乳腺癌恶性生物学行为中发挥的作用及其可能的调控机制。方法:利用OncomiR在线数据库分析miR-9-5p在乳腺癌组织与正常乳腺组织中表达的差异,qPCR检测乳腺癌细胞系与正常乳腺细胞中miR-9-5p表达水平。基于靶基因预测软件TargetScan分析ONECUT2(one cut homeobox 2)可能是miR-9-5p的作用靶基因,双荧光素酶报告实验验证两者的靶向关系。向MDA-231细胞中分别转染miR-9-5p mimic、ONECUT2 siRNA及相应对照,qPCR及WB实验检测转染对MDA-231细胞中干性基因NOTCH1、NANOG和Y染色体性别决定区(sex-determing region of Y chromosome,SRY)-盒转录因子9(SRY-box transcription factor 9,SOX9)表达水平的影响,BrdU法、AnnexinⅤ流式细胞术、MTS实验分别检测转染对细胞增殖、凋亡和化疗耐药的影响,ALDEFLUOR染色流式细胞术检测miR-9-5p及靶基因ONECUT2对肿瘤干细胞化特征的影响。建立NSG小鼠乳腺癌化疗模型,体内实验进一步验证ONECUT2对肿瘤干性化及化疗抵抗等肿瘤恶性生物学行为的影响。结果:miR-9-5p在乳腺癌组织(P=0.007)及乳腺癌MDA-231细胞系(P=0.0005)中呈现显著高表达,并与乳腺癌患者不良预后呈正相关(P=0.0016)。miR-9-5p可靶向负调控ONECUT2,进而增加ALDH+MDA-231细胞比例(P=0.0006),上调干性NOTCH1、NANOG和SOX9蛋白表达,并增强乳腺癌细胞抗凋亡能力(P=0.0003)及其对多西他赛(DTX)和多柔比星(DOXO)化疗的耐受性;然而miR-9-5p/ONECUT2轴未能显著影响MDA-231细胞的增殖能力(P>0.05)。与对照组相比,MDA-231/ONECUT2组小鼠接受DTX治疗后,移植瘤体积较对照组显著缩小(P<0.05),瘤组织中NOTCH1、SOX9蛋白和ABC转运蛋白的mRNA和蛋白表达水平均显著降低(P<0.05或P<0.01)。结论:乳腺癌组织中高表达的miR-9-5p通过靶向ONECUT2诱导乳腺癌干细胞化及抗凋亡能力,增强了其对化学治疗的抵抗性。展开更多
One cut domain family member 2(ONECUT2,OC-2,OC2),是ONECUT转录因子家族中第二个被发现的成员。OC2基因位于人类第18号染色体上,其蛋白结构特征是具有单一cut结构域和一个非典型同源结构域,可以与特定的DNA启动子序列结合,调控靶基...One cut domain family member 2(ONECUT2,OC-2,OC2),是ONECUT转录因子家族中第二个被发现的成员。OC2基因位于人类第18号染色体上,其蛋白结构特征是具有单一cut结构域和一个非典型同源结构域,可以与特定的DNA启动子序列结合,调控靶基因的表达。在最开始,人们发现ONECUT2可以通过调控细胞的增殖、迁移、黏附和分化来调节人体器官的发育。而随着研究的深入,人们发现ONECUT2与肿瘤的增殖、转移、血管生成和干性等密切相关。本文综述了ONECUT2在多种肿瘤中的表达情况和促癌机制,结合其小分子抑制剂的发现,该基因可能是肿瘤治疗的新靶点。展开更多
Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive...Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.展开更多
文摘In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by perma- nent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Miiller glial cells. Following injury, zebrafish Miiller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Mtiller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from ze- brafish and mammalian Mtiller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Mtiller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases.
文摘目的:探讨ONECUT2(one cut homeobox 2,OC-2)基因在人胃癌组织中的表达水平及其临床意义。方法:基于生物信息学技术全面检索Oncomine、GEPIA、CCLE、EBI数据库,分析OC-2在胃癌和其他种类肿瘤中的表达水平,用Kmplot数据库验证其表达水平与胃癌患者预后的关系,用STRING数据库构建蛋白互作网络(protein protein interaction network,PPI network),分析与胃癌相关的OC-2共表达基因。结果:在OC-2差异表达的不同种类肿瘤中,其表达水平一般上调。在胃癌组织和细胞中OC-2表达水平均显著升高(均P<0.05),且可能与组织分型和肿瘤分期无关(均P>0.05)。OC-2表达水平与胃癌患者的预后有关,OC-2低表达组胃癌患者的中位总生存期和中位无病生存期均显著高于高表达组(40.0 vs 26.5个月,26.2 vs 16.1个月;均P<0.01)。筛查获得了15个OC-2的共表达基因;构建的PPI网络预测了30个功能蛋白与OC-2蛋白相互作用,其中有11个蛋白基因也与胃癌的发生发展有关,Pearson相关分析后得出4个与OC-2密切正相关的蛋白基因:PDX1(R=0.49)、CREB1(R=0.31)、MAPK1(R=0.26)、CTSS(R=0.25)。结论:OC-2在胃癌发生发展及侵袭转移过程中可能起重要的作用,有望成为胃癌诊治和判断预后的重要指标和新的筛查靶点。
基金Research in the Mu lab is supported by grants from the National Eye Institute(EY020545)the SUNY/RF Research Collaboration Fundan unrestricted grant from Research to Prevent Blindness
文摘The retina and its development： The retina is an essential part of the visual system. A myriad of eye diseases are characterized by retinal degeneration, caused by either genetic or environmental factors. This underscores the importance of studying the genetic and molecular mechanisms that regulate the generation and maintenance of neurons in the mammalian retina. Our recent studies demonstrate that two related transcription factors Onecutl （Ocl） and Onecut2 （0c2） regulate multiple cell fates in the mouse retina, and their absence results in progressive retinal neurodegeneration （Wu et al., 2012, 2013; Sapkota et al., 2014）.
文摘目的:探讨miR-9-5p在乳腺癌恶性生物学行为中发挥的作用及其可能的调控机制。方法:利用OncomiR在线数据库分析miR-9-5p在乳腺癌组织与正常乳腺组织中表达的差异,qPCR检测乳腺癌细胞系与正常乳腺细胞中miR-9-5p表达水平。基于靶基因预测软件TargetScan分析ONECUT2(one cut homeobox 2)可能是miR-9-5p的作用靶基因,双荧光素酶报告实验验证两者的靶向关系。向MDA-231细胞中分别转染miR-9-5p mimic、ONECUT2 siRNA及相应对照,qPCR及WB实验检测转染对MDA-231细胞中干性基因NOTCH1、NANOG和Y染色体性别决定区(sex-determing region of Y chromosome,SRY)-盒转录因子9(SRY-box transcription factor 9,SOX9)表达水平的影响,BrdU法、AnnexinⅤ流式细胞术、MTS实验分别检测转染对细胞增殖、凋亡和化疗耐药的影响,ALDEFLUOR染色流式细胞术检测miR-9-5p及靶基因ONECUT2对肿瘤干细胞化特征的影响。建立NSG小鼠乳腺癌化疗模型,体内实验进一步验证ONECUT2对肿瘤干性化及化疗抵抗等肿瘤恶性生物学行为的影响。结果:miR-9-5p在乳腺癌组织(P=0.007)及乳腺癌MDA-231细胞系(P=0.0005)中呈现显著高表达,并与乳腺癌患者不良预后呈正相关(P=0.0016)。miR-9-5p可靶向负调控ONECUT2,进而增加ALDH+MDA-231细胞比例(P=0.0006),上调干性NOTCH1、NANOG和SOX9蛋白表达,并增强乳腺癌细胞抗凋亡能力(P=0.0003)及其对多西他赛(DTX)和多柔比星(DOXO)化疗的耐受性;然而miR-9-5p/ONECUT2轴未能显著影响MDA-231细胞的增殖能力(P>0.05)。与对照组相比,MDA-231/ONECUT2组小鼠接受DTX治疗后,移植瘤体积较对照组显著缩小(P<0.05),瘤组织中NOTCH1、SOX9蛋白和ABC转运蛋白的mRNA和蛋白表达水平均显著降低(P<0.05或P<0.01)。结论:乳腺癌组织中高表达的miR-9-5p通过靶向ONECUT2诱导乳腺癌干细胞化及抗凋亡能力,增强了其对化学治疗的抵抗性。
文摘One cut domain family member 2(ONECUT2,OC-2,OC2),是ONECUT转录因子家族中第二个被发现的成员。OC2基因位于人类第18号染色体上,其蛋白结构特征是具有单一cut结构域和一个非典型同源结构域,可以与特定的DNA启动子序列结合,调控靶基因的表达。在最开始,人们发现ONECUT2可以通过调控细胞的增殖、迁移、黏附和分化来调节人体器官的发育。而随着研究的深入,人们发现ONECUT2与肿瘤的增殖、转移、血管生成和干性等密切相关。本文综述了ONECUT2在多种肿瘤中的表达情况和促癌机制,结合其小分子抑制剂的发现,该基因可能是肿瘤治疗的新靶点。
文摘Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.
