NF-κB信号通路在食管鳞癌细胞增殖、抗凋亡中的作用机制及其阻断策略
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摘要
细胞信号传导通路的异常激活在促进肿瘤细胞生长、增殖，促进细胞运动、侵袭，抑制细胞凋亡，抵抗化疗和放疗的过程中起重要作用。研究表明，核因子-kappa B(Nuclear Factor-kappa B，NF-κB)信号通路在肿瘤发生、发展中起重要的作用，因而越来越受到人们的关注。
NF-κB在多种人类肿瘤中高表达，不同的Rel／NF-κB家族成员可以结合成不同的二聚体。在这些二聚体中，最常见的形式是由p50和p65组成的异源二聚体。在绝大多数静止期的细胞中，NF-κB与其阻抑物IκBs蛋白相结合，以非活性形式存在于细胞质中。NF-κB可以被多种刺激物所激活，如TNF-α、IL-1、放射线和某些化疗药物等，这些刺激物可以通过对IκBα的磷酸化而使其降解，并与NF-κB解离，暴露NF-κB的核识别位点，使其进入核内，促进下游靶基因的转录。
NF-κB的激活在细胞生存、粘附、分化和细胞生长中起关键作用，有研究表明，在一些人类肿瘤，如肝癌、肠癌和宫颈癌中NF-κB信号通路的激活在肿瘤的发生发展中起着重要的作用。而且，活化的NF-κB信号通路通过上调其下游的靶基因如COX2、cyclinD1、bc1-2等，促进肿瘤细胞的增殖，抑制肿瘤细胞的凋亡，提高肿瘤细胞对化疗药的耐受性。随着对信号传导机制及其异常与肿瘤关系研究的不断深入，人们逐渐认识到针对信号传导异常环节进行肿瘤治疗的重要性和可行性。在许多恶性肿瘤中，持续激活的和某些抗肿瘤药物诱发的NF-κB活化的特性，使得这个转录因子成为一个有前途的分子靶点。RNA干扰技术(RNA
interferene，RNAi)是目前研究基因功能强有力的工具之一，能够用于研究特定基因的表达抑制。同时一些天然化合物如姜黄素也可以抑制IKK／NF-κB的活性，
Aberrant activation of cell signaling pathway has been associated with proliferation, inhibitory apoptosis, invasive growth and metastasis of tumor cells as well as their elevated resistants to radiation and chemotherapy. Some studies have shown that NF-κB signaling pathway might be a new target for therapeutic strategies in cancers due to its role in carcinogenesis and development.
NF-κB is activated in many human tumors. The NF-κB/Rei family can form various homo- or hetero-dimers. However, the most studied form is a heterodimer of the p50 and p65 subunits predominant in many kinds of cells. In most normal cells, NF-κB is sequestered in an inactive form through its tight association with the cytoplasmic inhibitor proteins, called inhibitors of NF-κB (IκB), which is catalyzed by an IκB kinase (IKK). A variety of extracellular stimulus factors such as TNF-α, IL-1, radiation and some chemotherapeutic drugs trigger a common signal transduction pathway based on the phosphorylation and degradation of IκB to freely active NF-κB. The released activated NF-κB is rapidly translocated to the nucleus and binds to the promoter region in the relevant downstream genes to touch off a series of transcriptional events.
Constitutively activated NF-κB has been implicated in survival, adherence, transformation and proliferation of tumor cells. Activation of NF-κB has been
NF-κB在多种人类肿瘤中高表达，不同的Rel／NF-κB家族成员可以结合成不同的二聚体。在这些二聚体中，最常见的形式是由p50和p65组成的异源二聚体。在绝大多数静止期的细胞中，NF-κB与其阻抑物IκBs蛋白相结合，以非活性形式存在于细胞质中。NF-κB可以被多种刺激物所激活，如TNF-α、IL-1、放射线和某些化疗药物等，这些刺激物可以通过对IκBα的磷酸化而使其降解，并与NF-κB解离，暴露NF-κB的核识别位点，使其进入核内，促进下游靶基因的转录。
NF-κB的激活在细胞生存、粘附、分化和细胞生长中起关键作用，有研究表明，在一些人类肿瘤，如肝癌、肠癌和宫颈癌中NF-κB信号通路的激活在肿瘤的发生发展中起着重要的作用。而且，活化的NF-κB信号通路通过上调其下游的靶基因如COX2、cyclinD1、bc1-2等，促进肿瘤细胞的增殖，抑制肿瘤细胞的凋亡，提高肿瘤细胞对化疗药的耐受性。随着对信号传导机制及其异常与肿瘤关系研究的不断深入，人们逐渐认识到针对信号传导异常环节进行肿瘤治疗的重要性和可行性。在许多恶性肿瘤中，持续激活的和某些抗肿瘤药物诱发的NF-κB活化的特性，使得这个转录因子成为一个有前途的分子靶点。RNA干扰技术(RNA
interferene，RNAi)是目前研究基因功能强有力的工具之一，能够用于研究特定基因的表达抑制。同时一些天然化合物如姜黄素也可以抑制IKK／NF-κB的活性，
Aberrant activation of cell signaling pathway has been associated with proliferation, inhibitory apoptosis, invasive growth and metastasis of tumor cells as well as their elevated resistants to radiation and chemotherapy. Some studies have shown that NF-κB signaling pathway might be a new target for therapeutic strategies in cancers due to its role in carcinogenesis and development.
NF-κB is activated in many human tumors. The NF-κB/Rei family can form various homo- or hetero-dimers. However, the most studied form is a heterodimer of the p50 and p65 subunits predominant in many kinds of cells. In most normal cells, NF-κB is sequestered in an inactive form through its tight association with the cytoplasmic inhibitor proteins, called inhibitors of NF-κB (IκB), which is catalyzed by an IκB kinase (IKK). A variety of extracellular stimulus factors such as TNF-α, IL-1, radiation and some chemotherapeutic drugs trigger a common signal transduction pathway based on the phosphorylation and degradation of IκB to freely active NF-κB. The released activated NF-κB is rapidly translocated to the nucleus and binds to the promoter region in the relevant downstream genes to touch off a series of transcriptional events.
Constitutively activated NF-κB has been implicated in survival, adherence, transformation and proliferation of tumor cells. Activation of NF-κB has been
引文
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