Stat3 is required for the development of skin cancer

Pedranzini, Laura; Leitch, Andrea; Bromberg, Jacqueline

doi:10.1172/jci22800

Cited by 68 publications

(22 citation statements)

References 31 publications

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“…A previous report showed that gene ablation of STAT3 is required for cellular transformation and/or for tumor survival and growth of lymphoid cells by a deregulated tyrosine kinase 28 . Another group has shown, using a similar approach, that STAT3 is required for transformation and growth of skin tumors induced by chemical carcinogens 29 . The findings from new mouse model described in our present study further supports the tumorigenic role of STATs in cancer.…”

Section: Discussionmentioning

confidence: 99%

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

et al. 2016

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Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases as well liver. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knocked down led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the IL-6/STAT pathway in the STAT3 knockout (Ko) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 ppm in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis, and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex-vivo cultures of freshly-collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

et al. 2016

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“…Perhaps one of the best in vitro model of premalignancy for cancer prevention is STAT3 as suggested by the evidence, first that STAT3 plays a major role in oncogenesis and regarded as an oncogene (50–52); second, STAT3 is activated by an oncogenic Src (29, 50); third, STAT3 regulates transformation, inflammation, survival, proliferation and angiogenesis of the tumors through expression of c-myc, COX2, bcl-xl, survivin, cyclin D1 and VEGF respectively (53–56). Because our evidences indicate that gambogic acid downregulates STAT3 activation and STAT3-regulated gene expression, it suggests chemopreventive role of gambogic acid in an in vitro premalignancy model of cancer prevention.…”

Section: Discussionmentioning

confidence: 99%

Gambogic Acid Inhibits STAT3 Phosphorylation through Activation of Protein Tyrosine Phosphatase SHP-1: Potential Role in Proliferation and Apoptosis

Prasad

Pandey

Yadav

et al. 2011

Cancer Prevention Research

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The transcription factor, signal transducer and activator of transcription 3 (STAT3), is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Gamboge hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase (JAK) 1, and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced down-regulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by small interfering RNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis.

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“…IL-6 cytokines preferentially activate STAT-3, leading to dimerization, nuclear translocation, and binding to Interferon-Gamma [IFN-γ] Activated Site-like DNA elements (4). STAT-3 induces expression of genes that regulate anti-apoptotic behavior and proliferation such as Survivin , VEGF , c-Myc , and Cyclin D1 (6–8). …”

Section: Introductionmentioning

confidence: 99%

Loss of Protein Inhibitors of Activated STAT-3 Expression in Glioblastoma Multiforme Tumors: Implications for STAT-3 Activation and Gene Expression

Brantley¹,

Nabors

Gillespie³

et al. 2008

Clinical Cancer Research

168

150

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Purpose Signal Transducers and Activators of Transcription (STATs) activate transcription in response to numerous cytokines, controlling proliferation, gene expression and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including Globlastoma Multiforme (GBM), by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Little is known about the endogenous STAT inhibitors, the Protein Inhibitors of Activated STATs (PIAS) proteins, in human malignancies. The objective of this study was to examine the expression of STAT-3 and its negative regulator, PIAS3, in human tissue samples from control and GBM brains. Experimental Design Control and GBM human tissues were analyzed by immunoblotting and immunohistochemistry to determine the activation status of STAT-3 and expression of the PIAS3 protein. The functional consequence of PIAS3 inhibition by siRNA or PIAS3 over-expression in GBM cells was determined by examining cell proliferation, STAT-3 transcriptional activity and STAT-3 target gene expression. This was accomplished using 3H-TdR incorporation, STAT-3 dominant-negative constructs, RT-PCR and immunoblotting. Results and Conclusions STAT-3 activation, as assessed by tyrosine and serine phosphorylation, was elevated in GBM tissue compared to control tissue. Interestingly, we observed expression of PIAS3 in control tissue, while PIAS3 protein expression in GBM tissue was greatly reduced. Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation. Conversely, PIAS3 over-expression inhibited STAT-3 transcriptional activity, expression of STAT-3 regulated genes, and cell proliferation. We propose that the loss of PIAS3 in GBM contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation.

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Stat3 is required for the development of skin cancer

Cited by 68 publications

References 31 publications

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

Gambogic Acid Inhibits STAT3 Phosphorylation through Activation of Protein Tyrosine Phosphatase SHP-1: Potential Role in Proliferation and Apoptosis

Loss of Protein Inhibitors of Activated STAT-3 Expression in Glioblastoma Multiforme Tumors: Implications for STAT-3 Activation and Gene Expression

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