目的分析MAPK/MEK/ERK信号转导通路与急性主动脉夹层形成的关系及IKKε的调控作用,为临床相关治疗和新药研发提供参考。方法清洁级C57BL/6小鼠随机分为5组:对照组、模型组、IKKε-IN-1低剂量、中剂量和高剂量干预组。除对照组外,其余各...目的分析MAPK/MEK/ERK信号转导通路与急性主动脉夹层形成的关系及IKKε的调控作用,为临床相关治疗和新药研发提供参考。方法清洁级C57BL/6小鼠随机分为5组:对照组、模型组、IKKε-IN-1低剂量、中剂量和高剂量干预组。除对照组外,其余各组小鼠给予2 500 ng/(kg·min)血管紧张素Ⅱ(对照组给予生理盐水)14 d。自第7天起IKKε-IN-1低剂量、中剂量和高剂量干预组小鼠分别给予IKKε-IN-1治疗(1 mg/kg、5 mg/kg和25 mg/kg)。采用老龄小鼠埋泵缓释血管紧张素Ⅱ建立急性主动脉夹层动物模型,并采用IKKε特异性拮抗剂IKKε-IN-1进行干预,分析各组小鼠血浆MAPK/MEK/ERK信号转导通路相关蛋白表达。结果清洁级C57BL/6小鼠皮下植入缓释泵输注血管紧张素Ⅱ7 d后模型组小鼠收缩压为153±11.4 mm Hg(对照组为105±10.4 mm Hg),14 d后收缩压变为176±12.6 mm Hg,而IKKε-IN-1低剂量、中剂量和高剂量干预组小鼠的收缩压明显低于模型组(P<0.05),且呈剂量依赖性(P<0.05);与对照组相比,急性主动脉夹层小鼠Ras、Raf、MEK、ERK1/2、基质金属蛋白酶2(MMP2)及基质金属蛋白酶6(MMP6)蛋白表达明显增强而金属蛋白酶组织抑制因子1(TIMP1)和金属蛋白酶组织抑制因子2(TIMP2)的表达明显减弱(P<0.05),而IKKε-IN-1低剂量、中剂量和高剂量干预组上述蛋白的表达明显恢复(P<0.05),且呈剂量依赖性(P<0.05)。结论激活的MAPK/MEK/ERK信号转导通路及基质金属蛋白酶参与了急性主动脉夹层形成,且此过程与IKKε的调控密切相关。展开更多
1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导...1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导致MAPK信号通路组成型激活,该信号通路的异常激活与肿瘤微环境等机制促使NF1肿瘤发生。目前,主流的治疗方式包括针对Raf/MEK/ERK通路和/或mTOR通路的靶向抑制剂。近年来,对NF1的遗传学、临床特征、肿瘤起源、异常信号通路以及相关靶向抑制剂的疗效等方面的研究日益增多。深入了解NF1的病理生物学和分子机制将为开发更有效的靶向治疗方法提供坚实的基础。展开更多
The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this p...The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy.Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade.However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks.Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent.In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with a focus on MEK inhibitors.Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed.Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted and elaborately described on the basis of the latest research progress.Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.展开更多
文摘目的分析MAPK/MEK/ERK信号转导通路与急性主动脉夹层形成的关系及IKKε的调控作用,为临床相关治疗和新药研发提供参考。方法清洁级C57BL/6小鼠随机分为5组:对照组、模型组、IKKε-IN-1低剂量、中剂量和高剂量干预组。除对照组外,其余各组小鼠给予2 500 ng/(kg·min)血管紧张素Ⅱ(对照组给予生理盐水)14 d。自第7天起IKKε-IN-1低剂量、中剂量和高剂量干预组小鼠分别给予IKKε-IN-1治疗(1 mg/kg、5 mg/kg和25 mg/kg)。采用老龄小鼠埋泵缓释血管紧张素Ⅱ建立急性主动脉夹层动物模型,并采用IKKε特异性拮抗剂IKKε-IN-1进行干预,分析各组小鼠血浆MAPK/MEK/ERK信号转导通路相关蛋白表达。结果清洁级C57BL/6小鼠皮下植入缓释泵输注血管紧张素Ⅱ7 d后模型组小鼠收缩压为153±11.4 mm Hg(对照组为105±10.4 mm Hg),14 d后收缩压变为176±12.6 mm Hg,而IKKε-IN-1低剂量、中剂量和高剂量干预组小鼠的收缩压明显低于模型组(P<0.05),且呈剂量依赖性(P<0.05);与对照组相比,急性主动脉夹层小鼠Ras、Raf、MEK、ERK1/2、基质金属蛋白酶2(MMP2)及基质金属蛋白酶6(MMP6)蛋白表达明显增强而金属蛋白酶组织抑制因子1(TIMP1)和金属蛋白酶组织抑制因子2(TIMP2)的表达明显减弱(P<0.05),而IKKε-IN-1低剂量、中剂量和高剂量干预组上述蛋白的表达明显恢复(P<0.05),且呈剂量依赖性(P<0.05)。结论激活的MAPK/MEK/ERK信号转导通路及基质金属蛋白酶参与了急性主动脉夹层形成,且此过程与IKKε的调控密切相关。
文摘1型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常见的遗传性神经皮肤综合征,发病率为1/3500,主要表现为皮肤、神经、骨骼等多个系统的肿瘤形成。NF1基因突变导致神经纤维蛋白功能丧失,受神经纤维蛋白负调控的Ras信号失去抑制,导致MAPK信号通路组成型激活,该信号通路的异常激活与肿瘤微环境等机制促使NF1肿瘤发生。目前,主流的治疗方式包括针对Raf/MEK/ERK通路和/或mTOR通路的靶向抑制剂。近年来,对NF1的遗传学、临床特征、肿瘤起源、异常信号通路以及相关靶向抑制剂的疗效等方面的研究日益增多。深入了解NF1的病理生物学和分子机制将为开发更有效的靶向治疗方法提供坚实的基础。
基金funded by the Startup Foundation for Doctors of Shanxi Province (Grant No.SD1827)Startup Foundation for Doctors of Shanxi Medical University (Grant No.XD1824) to Y.Li+1 种基金National Natural Science Foundation of China (Grant No.81872147, 81572588)Guangdong Provincial Special Fund of Science Innovation Strategy (Grant No.180918104960680) to Y.Cui
文摘The RAS-RAF-MEK-ERK signaling pathway(MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers.As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy.Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade.However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks.Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent.In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with a focus on MEK inhibitors.Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed.Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted and elaborately described on the basis of the latest research progress.Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.
