Mining for JAK-STAT mutations in cancer

Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, Brussels B-1200, Belgium.
Trends in Biochemical Sciences (Impact Factor: 11.23). 04/2008; 33(3):122-31. DOI: 10.1016/j.tibs.2007.12.002
Source: PubMed


The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway mediates signaling by cytokines, which control survival, proliferation and differentiation of several cell types. Constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations. Recently, a unique somatic mutation in JAK2 was identified in a majority of patients with myeloproliferative neoplasms. This mutation, encoding a V617F substitution, promotes JAK2 catalytic activation and cytokine-independent signaling. JAK2 and JAK3 mutations have also been identified in a minority of polycythemia vera and acute megakaryoblastic leukemia patients, and it is predicted that further JAK-STAT mutations will be identified in different cancers. Recent discoveries also suggest that mutated JAK proteins will be potent targets for anti-cancer therapy.

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    • "In tumor cells, there is continuous STAT-3 activation, resulting in disordered janus tyrosine kinase (JAK)-STAT signal transduction, which is typical of tumor cells during invasion and metastasis (3). STAT-3 may be activated by a variety of cytokines, in particular, those in the interleukin (IL)-6 family, such as gp130 (4). Jenkins et al (5) found that STAT-3 deletion mutants completely reversed the splenomegaly, hepatic acute phase reaction, abnormal lymphocyte activation and spontaneous gastric antrum cancer observed in gp130 mutant mice, demonstrating that the sustained activation of STAT-3 is important for the abnormal proliferation of a variety of cells. "
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    ABSTRACT: The aim of the present study was to investigate the expression of proteins associated with the sustained activation of the signal transducer and activator of transcription (STAT)-3 pathway during diethylnitrosamine (DEN)-induced rat liver carcinogenesis. DEN was intermittently administered to rats to induce liver cancer, and light and electron microscopy were used to observe the morphological changes in the liver during carcinogenesis. Western blotting and quantitative polymerase chain reaction (qPCR) were used to detect the expression of STAT-3, phosphorylated (p)-STAT-3, matrix metalloproteinase (MMP)-10, vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), hypoxia inducible factor (HIF)-1α, basic fibroblast growth factor (bFGF) and interleukin (IL)-10, in order to investigate the association between STAT-3 and p-STAT-3 expression and MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10. The western blotting and qPCR results revealed that the expression of STAT-3, p-STAT-3, MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10 proteins gradually increased during carcinogenesis. Furthermore, the STAT-3 and p-STAT-3 levels were found to positively correlate with MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10 protein expression. During DEN-induced rat liver carcinogenesis, STAT-3 protein continually activated MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10, and its expression was found to positively correlate with the expression of these proteins.
    Full-text · Article · Aug 2014 · Oncology letters
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    • "Tumorigenesis associated with IL-6 has been attributed to the constitutive or aberrant activation of STAT3 (6). JAK/STAT signaling pathway is well-known to be important in the carcinogenesis of several cell types (7). Previous in vitro functional experiments using CaP cell lines have shown that STAT3 is constitutively active in these cell lines and promotes the metastatic progression of CaP (8,9). "
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    ABSTRACT: The aim of the present study was to analyze the molecular mechanisms involved in blocking the signaling pathway and the effects of this on the progression of prostate cancer (CaP) cells in vitro. LNCaP human CaP cell line was stimulated with interleukin-6 (IL-6) in the presence/absence of Janus kinase (JAK) 2 (AG490), signal transducer and activator of transcription 3 [(STAT3) S3I-201] inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Cytotoxic activity, the activation of phosphorylated (p)-STAT3 protein, caspase (CASP) 3 activity at protein level, vascular endothelial growth factor (VEGF) A, VEGFC, vascular endothelial growth factor receptor 2, STAT3, matrix metalloproteinase-2, myeloid cell leukemia sequence 1 (MCL-1), CASP8 and CASP9 messenger RNA (mRNA) levels were determined. Morphology and apoptosis were confirmed by DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. IL-6 rapidly induced the phosphorylation of STAT3 in a dose- and time-dependent manner with a peak expression at 3 h at a concentration of 25 ng/ml. In addition, AG490 (50 μM) and S3I-201 (300 μM) inhibited STAT3 activation. Western blotting results revealed that p-STAT3 protein expression decreased significantly with AG490 and S3I-201 treatment in LNCaP cells. AG490 and S3I-201 induced the downregulation of VEGFA, MCL-1 and STAT3 and the upregulation of CASP8 and CASP9 mRNA transcription levels. In addition, the inhibitors increased the level of CASP3 protein. Combinations of AG490- and S3I-201-TRAIL did not result in an increase in this effect. Parallel results were found by DAPI staining and TUNEL assay. To the best of our knowledge, this is the first study to investigate the possible clinical use of AG490 or S3I-201, together with the reduced use of chemotherapeutic agents with high cytotoxicity, for their ability to exert an apoptotic effect, targeting the JAK/STAT3 pathway.
    Full-text · Article · Mar 2014 · Oncology letters
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    • "Janus Kinase 2 (Jak2) is a member of cytoplasmic non-receptor tyrosine kinases and is activated through members of the tyrosine receptor super family as growth hormone or erythropoietin receptors [1]. A Guanine-to-Thymine transversion, which results in a substitution of valine to phenylalanine amino acid at codon 617 of Jak2 (JAK2V617F), is responsible for the constitutive activity of this tyrosine kinase that activates signal transducer and activator of transcription (STAT), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways, and transforms hematopoietic progenitor cells [2] [3] [4] [5]. "
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    ABSTRACT: Janus Kinase 2 (JAK 2) gene single point mutations, which have been reported to be associated with myeloproliferative disorders, are usually detected through conventional methods such as melting curve assays, allele-specific and quantitative Polymerase Chain Reactions (PCR). Herein, an electrochemical biosensor for the detection of a Guanine (G) to Thymine (T) transversion at nucleotide position 1849 of the JAK2 gene was reported. Due to clinical importance of this mutation, easy and sensitive tests are needed to be developed. Our aim was to design a biosensor system that is capable of detect the mutation within less than 1hour with high sensitivity. For these purposes, an electrochemical sensing system was developed based on detecting hybridization. Hybridization between probe and its target and discrimination of single point mutation was investigated by monitoring guanine oxidation signals observed at +1.0V with Differential Pulse Voltammetry (DPV) by using synthetic oligonucleotides and Polymerase Chain Reaction (PCR) amplicons. Hybridization between probe and PCR amplicons was also determined with Electrochemical Impedance Spectroscopy (EIS). We successfully detect hybridization first in synthetic samples, and ultimately in real samples involving blood samples from patients as well as additional healthy controls. The limit of detection (S/N=3) was calculated as 44 picomole of target sequence in a 40-μL reaction volume in real samples.
    Full-text · Article · Dec 2013 · Clinica chimica acta; international journal of clinical chemistry
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