文章：

重新审视STAT3信号在癌症中的作用：新的和意想不到的生物学功能

Revisiting STAT3 signalling in cancer: new and unexpected biological functions

原文发布日期：2014-10-24

DOI: 10.1038/nrc3818

类型: Review Article

开放获取: 否

要点：

1. The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins. JAK–STAT3 signalling is crucial for cancer development in both tumour cells and the tumour microenvironment, and both JAK and STAT3 have emerged as important targets for cancer treatment.
2. Interleukin-6 (IL-6) and several other members of the IL-6 family have a prominent role in JAK–STAT3 activation in cancer. Antibodies that target IL-6 are currently in clinical trials for cancer treatment. However, owing to a multitude of cytokines, growth factors and many other molecules that activate JAK–STAT3, blocking IL-6 and its family members alone is not likely to be sufficient for cancer treatment.
3. Several G-protein-coupled receptors (GPCRs) are found to activate STAT3 through JAKs, leading to cancer progression. GPCRs are more readily druggable than STAT3, which is a transcription factor and therefore difficult to target because it is mostly in the nucleus and lacks enzymatic activity.
4. Although Toll-like receptors (TLRs) are usually associated with immune activation, several of them are overexpressed and could promote cancer via the JAK–STAT3 pathway in both immune cells and tumour cells. The synthetic ligand of TLR9A, CpG oligonucleotide, when linked to small interfering RNA (siRNA) against STAT3, has been shown to be an effective approach to deliver RNA into both immune cells and tumour cells. The CpG–STAT3 siRNA is now poised to enter clinical trials for cancer treatment.
5. Some microRNAs that interact with the JAK–STAT3 pathway are emerging as having crucial roles in regulating cancer-promoting inflammation and oncogenesis. Appropriate microRNAs that can block the JAK–STAT3 pathway could potentially be developed as inhibitors of this pathway with clinical application.
6. Although STAT3 is well known as a transcription factor that defines a gene expression programme in cancer, recent studies have identified surprising roles of STAT3 in mitochondria in cancer. Importantly, STAT3 also contributes to cancer progression by DNA methylation and chromatin topological modulation.

要点翻译：

1. Janus激酶（JAK）是信号转导与转录激活因子（STAT）的主要激活剂。JAK-STAT3信号通路在肿瘤细胞和肿瘤微环境中的癌症发展过程中至关重要，因此JAK和STAT3已成为癌症治疗的重要靶点。
2. 白细胞介素-6（IL-6）及其家族多个成员在癌症的JAK-STAT3激活中发挥重要作用。靶向IL-6的抗体目前正处于癌症治疗的临床试验阶段。然而，由于存在多种细胞因子、生长因子及其他激活JAK-STAT3的分子，仅阻断IL-6及其家族成员可能不足以实现癌症治疗。
3. 研究发现多种G蛋白偶联受体（GPCR）通过JAK激活STAT3，从而促进癌症进展。与转录因子STAT3相比，GPCR更易于成为药物靶点——因为STAT3主要位于细胞核内且缺乏酶活性，难以被靶向干预。
4. 虽然Toll样受体（TLR）通常与免疫激活相关，但其中多个成员在免疫细胞和肿瘤细胞中通过JAK-STAT3通路过度表达并促进癌症发展。TLR9的合成配体CpG寡核苷酸与靶向STAT3的小干扰RNA（siRNA）连接后，已被证明能将RNA有效递送至免疫细胞和肿瘤细胞。CpG-STAT3 siRNA联合疗法目前即将进入癌症治疗临床试验阶段。
5. 某些与JAK-STAT3通路相互作用的microRNA在调控促癌性炎症和肿瘤发生中起关键作用。能够阻断JAK-STAT3通路的特定microRNA有望开发成该通路的抑制剂，并具有临床应用潜力。
6. 尽管STAT3作为定义癌症基因表达程序的转录因子广为人知，但最新研究发现STAT3在肿瘤线粒体中具有令人惊讶的功能。更重要的是，STAT3还通过DNA甲基化和染色质拓扑调控促进癌症进展。

英文摘要：

The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK–STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK–STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.

摘要翻译： 

Janus激酶（JAK）和信号转导与转录激活因子（STAT）蛋白，尤其是STAT3，是癌症治疗中最有前景的新靶点之一。除白细胞介素-6（IL-6）及其家族成员外，包括G蛋白偶联受体（GPCR）、Toll样受体（TLR）和微小RNA在内的多条通路也被新近证实可调节癌症中的JAK–STAT信号。JAK–STAT3信号不仅因其在肿瘤细胞增殖、存活、侵袭和免疫抑制中的作用而闻名，还通过炎症、肥胖、干细胞以及转移前微环境促进癌症发展。除作为癌症中转录因子的既定作用外，STAT3还调控线粒体功能，并通过表观遗传机制影响基因表达。新近发现的JAK–STAT3在肿瘤中的调节因子及其功能，是癌症治疗潜在策略的重要靶点。

原文链接：

Revisiting STAT3 signalling in cancer: new and unexpected biological functions