Mohana Kamari,1,*
1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.
Introduction: The JAK/STAT system controls the maintenance of stem cells, hematopoiesis, and the inflammatory response in addition to controlling embryonic development. Through several transmembrane receptor families, the route transmits signals from cytokines, interleukins, and growth factors. Erythropoietin and granulocyte colony-stimulating factor (G-CSF) receptors are examples of type I receptors. Granulocyte-macrophage colony-stimulating factor receptors are type IIa receptors, and interleukin-6 and leukaemia inhibitory factor receptors are members of the type IIb subfamily. These receptors' intracellular tails are inherently linked to janus kinases (JAKs), dormant kinases. The phosphorylation of certain tyrosine residues in receptor-associated JAKs, which occurs as a result of ligand interaction, transforms inactive JAKs into catalytically active JAKs. Ligand binding produces conformational changes in receptors that alter the alignment of receptor-associated JAKs, enabling phosphorylation of specific tyrosine residues that convert inactive JAKs into catalytically active tyrosine kinases. The aim of this study was to investigate The role of JAK/STAT signalling in cancer.
Methods: This review study has been written from scientific databases such as Science Direct, Springer, Google Scholar, and PubMed.
Results: Increased expression of the G-CSF receptor is observed in high-grade ovarian epithelial tumours, and experiments in cell culture suggest that G-CSF contributes to JAK/ STAT activation in this disease.Gain-of-function mutations in JAKs have been observed to cause pathway activation in haematological malignancies. More recently, large-scale sequencing efforts have identified genetic changes affecting JAKs in certain solid tumours. Missense mutations in JAK1 have been identified in 9% of patients with Hepatitis B-associated hepatocellular carcinoma, and validation in cell culture shows that these mutations increase phosphorylation of JAK1 and STAT3 and enable cytokine-independent growth. In gastric adenocarcinoma, a comprehensive molecular characterisation project has revealed frequent amplification of the chromosomal locus containing JAK2. Corresponding increases in JAK2 messenger RNA suggest that this may increaseJAK2 protein levels and pathway activity. Activating mutations in STATs, although generally rare, have been described in cancer. In large granular lymphocytic leukaemia,40% of patients have mutations affecting the SH2 domain of STAT3. These introduce hydrophobic residues thought to stabilize STAT dimers, and lead to increased STAT-responsive transcription. Amplification of the STAT5A/B locus has been described in prostate cancer, and is associated with increased expression and nuclear localisation of STAT5 in tumour samples. These amplifications increase cell survival in culture and promote tumour growth in a xenograft model.Reduced expression of negative regulators can cause increased pathway activation. In non-small cell lung cancer (NSCLC) tumour samples, expression of SOCS3 is lost due to promoter hypermethylation, an epigenetic change that reduces gene transcription.The impact of this on pathway activation was validated using a NSCLC cell line, where restoration of SOCS3 expression reduced constitutive STAT3 phosphorylation (He et al, 2003). The PIAS3 protein levels have been shown to be reduced in glioblastoma, possibly due to increased protein degradation. In glioblastoma tissue samples, low levels of PIAS3 are associated with increased pSTAT3 and increased expression of proteins produced from STAT target genes.
Conclusion: The JAK/STAT signaling system is very active in many solid tumors, according to a direct study of tissue samples. Since JAK/STAT signaling plays a crucial role in a network of signaling pathways that are dysregulated in cancer, it is possible to use targeted suppression of JAK/STAT signaling as a therapeutic strategy to treat patients with solid tumours. Targeting JAK/STAT activation inhibitors at these patient populations is anticipated to be especially effective.
Keywords: JAK/STAT signaling, cancer, STAT5, chromosomal locus