Importance of STAT3 signalling in cancer, metastasis and therapeutic interventions.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is encoded on chromosome 17q21. The SH2 and the DNA binding domains are critical structural components of the protein, together with tyrosine and serine residues that initiate phosphorylation. STAT3 interacts with DNA directly and functions in cells as both a signal transducer and a transcription factor. Its cytoplasmic activation results in dimerisation and nuclear translocation, where it is involved in the transcription of a large number of target genes. STAT3 is hyperactive in cancer cells as a result of upstream STAT3 mutations or enhanced cytokine production in the tumour environment. The STAT3 signalling pathway promotes many hallmarks of carcinogenesis and metastasis, including enhanced cell proliferation and survival, as well as migration and invasion into the extracellular matrix. Recent investigations into novel STAT3-based therapies describe a range of innovative approaches, such as the use of novel oligonucleotide drugs. These limit STAT3 binding to its target genes by attaching to SH2 and DNA-binding domains. Yet, despite these significant steps in understanding the underpinning mechanisms, there are currently no therapeutic agents that addresses STAT3 signalling in a clinically relevant manner. • Cytokine binding and interaction with cell membrane receptors activates proteins of the STAT family and leads to regulation of gene transcription, this activation is mediated by the Janus-Kinase (JAK) family of proteins, many of which are enzymes found in mammalian cells (JAK1, JAK2, JAK3 and TYK2). • They phosphorylate specific STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6), bringing about dimerisation and nuclear translocation. Aberrant activation of STAT family proteins occurs in a broad range of cancer types with a high degree of STAT3 activation, in particular, found in many human tumour tissues and cancerous cell lines. • For example, in B-cell lymphoma and cervical cancer, STAT3 activation has been linked to poor prognosis. • Activation is also linked to carcinogenesis and accelerated invasion. • STAT3 signalling and its role in cancer and metastasis will be examined in this article. [ABSTRACT FROM AUTHOR]