Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Cytokine Growth Factor Rev. 2010 Feb;21(1):11-9. doi: 10.1016/j.cytogfr.2009.11.005. Epub 2009 Dec 16.
Transcriptional factors of the NF-kappaB family and STAT3 are ubiquitously expressed and control numerous physiological processes including development, differentiation, immunity, metabolism and cancer. Both NF-kappaB and STAT3 are rapidly activated in response to various stimuli including stresses and cytokines, although they are regulated by entirely different signaling mechanisms. Once activated, NF-kappaB and STAT3 control the expression of anti-apoptotic, pro-proliferative and immune response genes. Some of these genes overlap and require transcriptional cooperation between the two factors. The activation of and interaction between STAT3 and NF-kappaB plays a key role in controlling the dialog between the malignant cell and its microenvironment, especially with inflammatory/immune cells that infiltrate tumors. Quite often, cytokines whose expression is induced in response to NF-kappaB in immune cells of the tumor microenvironment lead to STAT3 activation in both malignant and immune cells. While within malignant and pre-malignant cells STAT3 exerts important oncogenic functions, within inflammatory cells it may also suppress tumor promotion through its anti-inflammatory effects. Other interactions and forms of crosstalk between NF-kappaB and STAT3 include physical interaction between the two, cooperation of these factors at gene promoters/enhancers, the NF-kappaB dependent expression of inhibitors of STAT3 activation and the participation of STAT3 in inflammatory cells in the negative regulation NF-kappaB. Despite these versatile and occasionally antagonistic interactions, NF-kappaB and STAT3 cooperate to promote the development and progression of colon, gastric and liver cancers. In addition to explaining the molecular pathogenesis of cancer, these interactions also offer opportunities for the design of new therapeutic interventions.
NF-κB 家族和 STAT3 的转录因子广泛表达，控制着许多生理过程，包括发育、分化、免疫、代谢和癌症。NF-κB 和 STAT3 都能迅速被各种刺激物（包括应激和细胞因子）激活，尽管它们受到完全不同的信号机制的调节。一旦被激活，NF-κB 和 STAT3 控制着抗凋亡、促增殖和免疫反应基因的表达。其中一些基因重叠，需要两个因子之间的转录合作。STAT3 和 NF-κB 的激活和相互作用在控制恶性细胞与其微环境之间的对话中起着关键作用，特别是与浸润肿瘤的炎症/免疫细胞。通常情况下，细胞因子在肿瘤微环境中的免疫细胞中响应 NF-κB 而被诱导表达，导致恶性细胞和免疫细胞中的 STAT3 激活。虽然在恶性和癌前细胞中 STAT3 发挥着重要的致癌功能，但在炎症细胞中，它也可能通过其抗炎作用抑制肿瘤的促进。NF-κB 和 STAT3 之间的其他相互作用和串扰形式包括两者之间的物理相互作用、这些因子在基因启动子/增强子上的合作、NF-κB 依赖的 STAT3 激活抑制剂的表达以及 STAT3 在炎症细胞中的参与对 NF-κB 的负调控。尽管这些作用具有多样性且有时具有拮抗作用，但 NF-κB 和 STAT3 合作促进了结肠、胃和肝癌的发展和进展。除了解释癌症的分子发病机制外，这些相互作用还为设计新的治疗干预措施提供了机会。
