NF-κB Functions in Tumor Initiation by Suppressing the Surveillance of Both Innate and Adaptive Immune Cells

Wang, David J.; Ratnam, Nivedita M.; Byrd, John C.; Guttridge, Denis C.

doi:10.1016/j.celrep.2014.08.049

Cited by 62 publications

(52 citation statements)

References 44 publications

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“…It has been shown that neutrophils exposed to a combination of G-CSF and IL-6 converted BM neutrophils from a tumor-suppressive to a tumorpromoting phenotype (42). NF-κB-mediated increases in myeloidderived suppressor cells were shown to have a major role in tumor angiogenesis and immune modulation (43). This could underlie the advantage for the tumor cell growth we see in Tle1 Δ/Δ mice.…”

Section: Discussionmentioning

confidence: 75%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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Section: Discussionmentioning

confidence: 75%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although established as an oncogene during the late stages of cancer progression, comparatively little is known about the effects of this pathway at the earlier stages of tumor development. Recent work from our laboratory showed that NF-κB functions as an oncogene by protecting Ras-expressing transformed cells from the actions of infiltrating innate immune cells (10). However, the mechanism by which NF-κB evades the antitumor effects of macrophages has not been established.…”

Section: Introductionmentioning

confidence: 99%

“…Work from our laboratory and others have shown that macrophages mediate their killing activity through secretion of the proapoptotic factors TNF and NO (10,18). To confirm this in pancreatic tumor cells, we treated KPC Δp65 both genes ( Figure 7A and Supplemental Figure 7A).…”

Section: Gdf-15 Suppresses Macrophage Cytotoxic Activity By Inhibitinmentioning

confidence: 99%

“…We recently discovered that transformed cells containing NF-κB are capable of circumventing the antitumor activity of activated macrophages (10). To determine whether this protective activity was mediated through a soluble factor, we utilized a coculture system containing peritoneal macrophages along with …”

Section: Gdf-15 Protects Transformed Cells Against Macrophage-mediatementioning

confidence: 99%

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NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Ratnam¹,

Peterson

Talbert

et al. 2017

Journal of Clinical Investigation

126

102

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“…23 This is of interest as NF-κB targets many pro-cancerous genes and plays a vital role in immune response as well. 53 Our study also showed that ectopic overexpression of EPSTI1 in the two noninvasive cell lines, MCF-7 and Implications of epithelial-stromal interaction 1…”

Section: Introductionmentioning

confidence: 66%

Implications of Epithelial–Stromal Interaction 1 in Diseases Associated with Inflammatory Signaling

Gray

Zhao

2016

Cell Communication Insights

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Epithelial-stromal interaction 1 (EPSTI1) was initially identified as an induced gene in breast cancer epithelial cells by cocultured stromal fibroblasts. This discovery led to further investigation and understanding of the role of EPSTI1 in cancer. Aberrant elevation of EPSTI1 occurs primarily in invasive breast cancer epithelial cells. Forced overexpression of EPSTI1 in noninvasive cancer cells can substitute for the stromal fibroblasts. EPSTI1 was further implicated in cancer by our most recent study that identified it as one of the few most upregulated genes in human breast cancer by Krüppel-like factor 8 (KLF8), a pro-cancerous transcription factor in many cancer types. Our study also demonstrated that EPSTI1 interacts with valosin-containing protein to promote the degradation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) inhibitor alpha, leading to the activation and nuclear translocation of NF-κB. Additionally, EPSTI1 was shown to inhibit apoptosis by inactivating caspase 8. Studies on hepatitis C and E viruses have indicated that EPSTI1 plays a role in inhibition of the viral replication by promoting the expression of protein kinase R or protein kinase RNA-activated, a viral response gene, suggesting a role of EPSTI1 in immune response. Interestingly, in addition to transducing stromal signals, EPSTI1 has been implicated in immune privilege and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and histiocytic necrotizing lymphadenitis. This review seeks to comb EPSTI1-related studies as it was cloned a dozen years ago with a particular focus on the mechanisms of its regulation and signaling, as well as its potential roles in the diseases.

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NF-κB Functions in Tumor Initiation by Suppressing the Surveillance of Both Innate and Adaptive Immune Cells

Cited by 62 publications

References 44 publications

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Implications of Epithelial–Stromal Interaction 1 in Diseases Associated with Inflammatory Signaling

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NF-κB Functions in Tumor Initiation by Suppressing the Surveillance of Both Innate and Adaptive Immune Cells

Cited by 62 publications

References 44 publications

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Implications of Epithelial&ndash;Stromal Interaction 1 in Diseases Associated with Inflammatory Signaling

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Implications of Epithelial–Stromal Interaction 1 in Diseases Associated with Inflammatory Signaling