Article

STATs in cancer, inflammation and immunity: A leading role of STAT3

Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 11/2009; 9(11):798-809. DOI: 10.1038/nrc2734
Source: PubMed

ABSTRACT

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

Download full-text

Full-text

Available from: Hua Yu, May 15, 2014
  • Source
    • "The data revealed that the JAK–STAT pathway is among the most mutated signal transduction pathways in cancer and therefor was coined by Bert Vogelstein as one of the 12 core cancer path- ways[119]. Not only does JAK–STAT contribute to most if not all hallmarks of cancer120121122123124, it also acts in a cell type-specific and mutational context-dependent fashion to display tumour suppressive as well as oncogenic properties. In the following we summarize the known contributions of TYK2 to the hallmarks and enabling characteristics of cancer (see Table 2)[122,125]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of-function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genome-wide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis. Due to its cytokine signalling functions TYK2 was found to be essential in tumour surveillance. Lately TYK2 activating mutants and fusion proteins were detected in patients diagnosed with leukaemic diseases suggesting that TYK2 is a potent oncogene. Here we review the cell intrinsic and extrinsic functions of TYK2 in the characteristics preventing and enabling carcinogenesis. In addition we describe an unexpected function of kinase-inactive TYK2 in tumour rejection.
    Full-text · Article · Nov 2015 · Cytokine
  • Source
    • "Signal transducer and activator of transcription (STAT) activation within tumor cells contributes to prosurvival phenotypes[113,114]. Signal transducer and activator of transcription 3 (STAT3) plays important roles in tumor cell proliferation, survival, invasion and immunosuppression[115,116]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor and cell stress-related gene. NDRG2 is associated with tumor incidence, progression, and metastasis. NDRG2 regulates tumor-associated genes and is regulated by multiple conditions, treatments, and protein/RNA entities, including hyperthermia, trichostatin A and 5-aza-2'-deoxycytidine, which are promising potential cancer therapeutics. In this review, we discuss the expression as well as the clinical and pathological significance of NDRG2 in cancer. The pathological processes and molecular pathways regulated by NDRG2 are also summarized. Moreover, mechanisms for increasing NDRG2 expression in tumors and the potential directions of future NDRG2 research are discussed. The information reviewed here should assist in experimental design and increase the potential of NDRG2 as a therapeutic target for cancer.
    Full-text · Article · Oct 2015 · Oncotarget
  • Source
    • "Treatment of Spry124 À/À MEFs with a MEK inhibitor, PD0325901 (Barrett et al., 2008), led to a dose-dependent reduction in Erk activation, and reduced baseline expression of five out of seven Spry124 À/À target genes tested to Spry124 fl/fl levels, indicating their dependence on Erk signaling (Figures 1E and S1F). We also noted that a number of Spry124 À/À targets, including Ccl2 and Fgf2, are Stat3 target genes (Yu et al., 2009), suggesting that Stat3, an oncogenic TF activated by RTK signaling, may be aberrantly activated upon Spry loss. Accordingly, Spry124 À/À MEFs displayed elevated constitutive phosphorylation of Stat3 tyrosine 705 and enhanced FGFinduced phosphorylation of Stat3 serine 727 (Figure S1G). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRas(G12V) or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, although both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRas(G12V) transformation or Sprouty deletion are largely distinct. Oncogenic HRas(G12V) elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRas(G12V)-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Reports
Show more