Haura EB, Turkson J, Jove R.. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2: 315-324
ABSTRACT Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.
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- "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. Haura et al (6) showed that the expression of the STAT-3 mutant, STAT-3-C (with cysteine substitutions at amino acids at A661 and N663), is carcinogenic, further confirming that the sustained activation of STAT-3 leads to cell transformation, which is closely associated with human carcinogenesis. In the present study, the diethylnitrosamine (DEN)-induced rat liver cancer model was used to simulate the induction and development of human liver cancer. "
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.Oncology letters 08/2014; 8(2):608-614. DOI:10.3892/ol.2014.2194 · 0.99 Impact Factor
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- "In OvCa, increased STAT3 directed transcription has been implicated in the stimulation of proliferation seen in response to cytokines, including VEGF and IL-6, in invasiveness  and as a predictor of poor prognosis . It activates the transcription of a number of genes, including antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1 , , . Moreover, constitutive activation of the STAT3 pathway has recently been shown to confer resistance to chemotherapy-induced apoptosis in epithelial malignancies –. "
ABSTRACT: This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO), a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04) in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF) induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2×106) were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001) in the peritoneal cavity compared to vehicle (phosphate buffered saline) treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO) for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.PLoS ONE 06/2014; 9(6):e97897. DOI:10.1371/journal.pone.0097897 · 3.23 Impact Factor
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- "It indicates that STAT3 is activated in GnT-V overexpression cells compared with Mock cells. It is well known that activated STAT3 can regulate the transcription of its target genes, which play important roles in the processes of oncogenesis including tumor angiogenesis, tumor cell invasion and metastasis . In addition, STAT3 could bind with other transcription factors such as specificity protein 1 (Sp1), regulating a number of pathways important to tumorgenesis . "
ABSTRACT: Receptor-like protein tyrosine phosphatases (RPTPs) are type I transmembrane glycoproteins with N-glycans whose catalytic activities are regulated by dimerization. However, the intrinsic mechanism involved in dimerizing processes remains obscure. In this study, receptor protein tyrosine phosphatase rho (PTPRT) is identified as a novel substrate of N-Acetylglucosaminyltransferase V (GnT-V). We show that addition of β1,6 GlcNAc branches on PTPRT prolongs PTPRT's cell-surface retention time. GnT-V overexpression enhances galectin-3's cell-surface retention and promotes PTPRT's dimerization mediated by galectin-3. Increased dimerization subsequently reduces PTPRT's catalytic activity on the dephosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyrosine residue 705 (pY705 STAT3), then the accumulated pY705 STAT3 translocates into the nucleus. Collectively, these findings provide an insight into the molecular mechanism by which GnT-V promotes cell migration, suggesting that accumulation of β1,6 GlcNAc branched N-glycans promotes PTPRT's dimerization and decreases its catalytic activity, resulting in enhanced cell migratory capacity.PLoS ONE 05/2014; 9(5):e98052. DOI:10.1371/journal.pone.0098052 · 3.23 Impact Factor