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Revisiting STAT3 signalling in cancer: new and unexpected biological functions

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

Abstract

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.

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Figure 1: Pathways activating JAK–STAT3 signalling in cancer.
Figure 2: STAT3–microRNA regulatory circuits.
Figure 3: Newly identified roles of JAK–STAT3 in cancer.

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Acknowledgements

The authors thank many laboratories and members of their own groups that have made important discoveries on the topics of JAK/STAT pathways in cancer. Special thanks also go to those individuals whose publications are relevant to the topics in this Review but which were not cited owing to space limitations.

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Correspondence to Hua Yu or Heehyoung Lee or Richard Jove.

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Glossary

Immune checkpoint

A pathway or molecule that is capable of inhibiting immune responses. In normal physiology, immune checkpoints are crucial for maintenance of self-tolerance to minimize unwanted collateral tissue damage. However, they also act as brakes for desired antitumour immune responses when subverted by tumours.

Toll-like receptors

(TLRs). TLRs consist of multiple family members that have an important role in the innate immune system responses and are usually expressed in immune cells such as macrophages and dendritic cells. TLRs recognize many molecules that are associated with pathogens, such as bacterial cell-surface lipopolysaccharides, double-stranded RNA of viruses, and the unmethylated CpG islands of bacterial and viral DNA.

MicroRNAs

(miRNAs). Short non-coding RNAs with the ability to regulate gene expression at transcriptional and post-transcriptional levels. miRNA can silence genes owing to its capacity to base-pair with complementary sequences within mRNA strands, thereby preventing translation of the mRNA into protein.

G-protein-coupled receptors

(GPCRs). Membrane proteins with a broad range of functions in biological species throughout evolution. They are regulated by binding to the nucleotides GTP and GDP. Stimulation by external signalling molecules activates GPCRs via exchange of GDP for GTP, leading to their interaction with associated G subunit proteins that propagate intracellular signals.

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Yu, H., Lee, H., Herrmann, A. et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14, 736–746 (2014). https://doi.org/10.1038/nrc3818

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