文章：

STAT3在癌症炎症和免疫中的主导作用

STATs in cancer inflammation and immunity: a leading role for STAT3

原文发布日期：2009-11-01

DOI: 10.1038/nrc2734

类型: Review Article

开放获取: 否

要点：

1. Signal transducer and activator of transcription (STAT) proteins have dual roles: they transduce signals through the cytoplasm and function as transcription factors in the nucleus. Although some STAT proteins such as STAT1 increase anti-tumour immunity, STAT3 and others induce cancer-promoting inflammation.
2. STAT3 signalling is a major intrinsic pathway for cancer inflammation owing to its frequent activation in malignant cells and key role in regulating many genes crucial for cancer inflammation in the tumour microenvironment.
3. Persistent activation of STAT3, and to a lesser extent STAT5, in diverse human cancers increases proliferation, survival, angiogenesis and metastasis, while also inhibiting anti-tumour immunity.
4. Many STAT3-regulated genes encode cytokines and growth factors, the receptors of which in turn activate the same STAT3 pathways, thereby propagating a stable feedforward loop between tumour cells and non-transformed stromal cells, including myeloid cells and T cells, promoting inflammatory responses that further support tumour growth and survival.
5. Interleukin-6 (IL-6)–Janus kinase (JAK)–STAT3 signalling is important for cancers resulting from the activation of the intrinsic inflammatory pathway owing to genetic or epigenetic changes in tumour cells. Extrinsic environmental inflammatory factors such as sunlight, pathogens and chemical carcinogens can also activate STAT3 through different mechanisms.
6. STAT3 interacts with nuclear factor-κB (NF-κB) at multiple levels and is activated by several NF-κB-regulated gene products, including IL-6. These two transcription factors regulate a multitude of genes important for STAT3 activation and cancer-promoting inflammation.
7. STAT1-driven anti-tumour immune responses and STAT3-mediated immune modulatory pathways can be mutually antagonistic, suggesting that therapeutic interventions targeting specific STATs can tip this balance to convert tumour-promoting inflammation to anti-tumour immune responses. Therefore, STAT3 has emerged as a crucial target for cancer therapy and STAT3 inhibitors are actively being developed.
8. Several tyrosine kinase inhibitors already in the clinic reduce STAT3 signalling by various mechanisms, thereby inducing tumour cell apoptosis and modulating inflammation in the tumour microenvironment in favour of therapeutic responses.

要点翻译：

1. 信号转导与转录激活因子（STAT）蛋白具有双重功能：它们在细胞质中转导信号，并在细胞核内作为转录因子发挥作用。虽然STAT1等蛋白能增强抗肿瘤免疫力，但STAT3及其他成员则会诱导促癌性炎症反应。
2. STAT3信号通路是癌症炎症的主要内在途径，因其在恶性细胞中频繁激活，且在调控肿瘤微环境中众多癌症炎症关键基因中起核心作用。
3. 在多种人类癌症中，STAT3的持续激活（以及程度较轻的STAT5）会促进细胞增殖、存活、血管生成和转移，同时抑制抗肿瘤免疫。
4. 许多STAT3调控的基因编码细胞因子和生长因子，其受体又可激活相同的STAT3通路，从而在肿瘤细胞与非转化基质细胞（包括髓系细胞和T细胞）之间形成稳定的前馈循环，促进炎症反应，进一步支持肿瘤生长和存活。
5. 白细胞介素-6（IL-6）-Janus激酶（JAK）-STAT3信号通路对于因肿瘤细胞遗传或表观遗传改变激活内在炎症途径所致的癌症至关重要。外界环境炎症因素（如日光、病原体和化学致癌物）也能通过不同机制激活STAT3。
6. STAT3与核因子κB（NF-κB）在多个层面相互作用，并被多种NF-κB调控的基因产物（包括IL-6）激活。这两种转录因子共同调控众多对STAT3激活和促癌性炎症至关重要的基因。
7. STAT1驱动的抗肿瘤免疫应答与STAT3介导的免疫调节通路可能相互拮抗，这表明针对特定STAT的治疗干预可打破平衡，将促癌性炎症转化为抗肿瘤免疫应答。因此，STAT3已成为癌症治疗的关键靶点，STAT3抑制剂的研发正积极推进。
8. 现有多种酪氨酸激酶抑制剂通过不同机制降低STAT3信号传导，从而诱导肿瘤细胞凋亡并调节肿瘤微环境中的炎症反应以增强治疗效果。

英文摘要：

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-κB (NF-κB) and interleukin-6 (IL-6)–GP130–Janus kinase (JAK) pathways, and by opposing STAT1- and NF-κB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

摘要翻译： 

与其在调控细胞因子依赖性炎症与免疫中的角色相称，信号转导与转录激活蛋白（STAT）在决定肿瘤微环境中免疫反应是促进还是抑制癌症方面处于核心地位。持续激活的STAT3，以及在较小程度上的STAT5，可增强肿瘤细胞的增殖、存活与侵袭，同时抑制抗肿瘤免疫。STAT3的持续激活还介导促肿瘤炎症。STAT3通过在肿瘤炎症与免疫中发挥双重作用：一方面促进包括核因子-κB（NF-κB）和白细胞介素-6（IL-6）–GP130–Janus激酶（JAK）通路在内的促癌炎症通路，另一方面拮抗由STAT1和NF-κB介导的T辅助1型抗肿瘤免疫反应。因此，STAT3是重定向炎症用于癌症治疗的有前景的靶点。

原文链接：

STATs in cancer inflammation and immunity: a leading role for STAT3