Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma

Martinović, Katarina Mirjačić; Srdiċ-Rajiċ, Tatjana; Babović, Nada; Džodić, Radan; Jurišić, Vladimir; Konjević, Gordana

doi:10.1136/jclinpath-2015-203107

Cited by 15 publications

(8 citation statements)

References 36 publications

(27 reference statements)

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“…IRF1, also called interferon regulatory factor 1, is encoded by the IRF1 gene in humans 3. As a transcription factor, IRF1 is the first member of the interferon regulatory factor family 4. IRF1 was originally thought to be a transcription factor that activates the expression of β-interferon and was subsequently confirmed to have a role in the transcriptional activation and repression of its target genes 5.…”

Section: Introductionmentioning

confidence: 99%

IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the Ras-Rac1 pathway

Hong

Zhang

Chen

et al. 2018

CMAR

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BackgroundInterferon regulatory factor 1 (IRF1) plays a role in the immune response, cellular necrosis, DNA damage, and DNA repair, offering an attractive target for anticancer treatment. However, little is known about the role of IRF1 in the regulation of CRC progression.MethodsQuantitative reverse transcription-PCR, Western blot, and immunohistochemistry were used to examine the expression level of IRF1; Cell Counting Kit-8, migration assay, and xenograft mouse models were used to examine the function of IRF1 in CRC cell lines; a ChIP assay was used to examine the binding between IRF1 and Ras association domain-containing protein 5 (RASSF5).ResultsIRF1 expression was lower in colorectal cancer (CRC) than in normal mucosa and the IRF1 expression level was inversely associated with CRC metastasis. In addition, IRF1 could inhibit CRC cell proliferation, migration, and metastasis in vivo and in vitro; IRF1 also induced cell cycle arrest but had no effect on cell apoptosis. IRF1 enhanced the expression of RASSF5 by increasing its promoter activity. Moreover, this study revealed a novel mechanism for inhibiting the RAS-RAC1 pathway by overexpression of RASSF5.ConclusionAltogether, the results indicate that IRF1, which promotes RASSF5 expression, suppresses CRC metastasis and proliferation possibly through downregulation of the RAS-RAC1 pathway.

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Section: Introductionmentioning

confidence: 99%

IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the Ras-Rac1 pathway

Hong

Zhang

Chen

et al. 2018

CMAR

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“…Several recent studies have shown that blocking STAT3 activation in tumor cells enhances NK cell-mediated antitumor efficacy by upregulating the levels of NKG2D ligands, such as MULT1, RAE1, H60 and MICA/B, or by suppressing IL-10 and TGF-β, which negatively regulate NK cell function [ [31] , [32] , [33] , [34] ]. STAT signaling especially constitutive STAT3 activation was associated with an impaired NK cell function in tumor patients not only in animal model [ 15 , 35 ]. Another study reported that STAT3 inhibition combined with the treatment of STING agonist increased the number of CD8 + T cells while decreasing those of regulatory T cells and myeloid-derived suppressor cells in TME [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that inhibition of aberrant STAT3 activation or deletion of STAT3 in mice suppresses tumor progression by improving antitumor immune responses [ [12] , [13] , [14] ]. Besides, STAT signaling also plays important roles in regulation of innate immunity of human population especially in people with tumors [ 15 ]. Furthermore, many clinical and/or preclinical studies have also shown that the anti-inflammatory agents used to target cancer-related inflammation enhance the effects of immunotherapies and suppress cancer progression [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

Dong

et al. 2021

Translational Oncology

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Inflammatory IL-6/STAT3 signaling is constitutively activated in diverse cancers and is associated with malignant cell proliferation, invasion and escape of antitumor immunosurveillance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is commonly used to treat insulin-resistant diabetes. In this study, for the first time, we showed that liraglutide remarkably improved the antitumor immune responses in hepatocellular carcinoma (HCC). Furthermore, we showed that the antitumor activity was mediated by nature killer cells (NKs) but not CD8 + T cells. Finally, we showed that liraglutide enhanced NK-mediated cytotoxicity by suppressing the IL-6/STAT3 signaling pathway in HCC cells. Our findings unveil a novel therapeutic role of liraglutide by manipulating the innate immunity in cancer therapy.

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“…A central role has been attributed to IRF‐1 and IFN‐stimulated genes in the so‐called “immunologic constant of rejection,” a signature upregulated in regressing melanoma metastases after immunotherapy that plays a central role in orchestrating the immune response and generating the switch from chronic to acute inflammation also in several immune‐mediated tissue destruction processes . A recent paper showed that metastatic melanoma patients have significantly lower Irf1 gene expression in PBMC, which was associated to decreased expression of the cytotoxic molecule perforin and lower levels of IFN‐γ production and pSTAT‐1, pSTAT‐4, pSTAT‐5 compared with healthy donors, indicating a cancer‐associated immunosuppression that may facilitate tumor progression …”

Section: Discussionmentioning

confidence: 99%

Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide

Buccione

Fragale

Polverino

et al. 2017

Intl Journal of Cancer

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The antitumor effectiveness of cyclophosphamide (CTX) and other chemotherapeutics was shown to rely not only on direct cytotoxicity but also on immunogenic tumor cell death and systemic immunomodulatory mechanisms, including regulatory T cell (Treg) depletion, Th1 cell polarization, type I interferon (IFN) and proinflammatory cytokine production. IFN regulatory factor (IRF)-1 is a transcriptional regulator of IFNs and IFN-inducible genes, involved in the control of Th1 and Treg differentiation and in sterile inflammation. Aim of this study was to explore the role of IRF-1 in CTX-induced antitumor effects and related immune activities. This study shows for the first time that IRF-1 is important for the antitumor efficacy of CTX in mice. Moreover, experiments in tumor-bearing C57BL/6 mice showed that Irf1 gene expression in the spleen was transiently increased following CTX administration and correlated with the induction of Th1 cell expansion and of Il12p40 gene expression, which is the main Th1-driving cytokine. At the same time, CTX administration reduced both Foxp3 expression and Treg cell percentages. These effects were abrogated in Irf1 mice. Further experiments showed that the gene and/or protein expression of caspase-1, iNOS, IL-1β, IL-6 and CXCL10 and the levels of nitric oxide were modulated following CTX in an IRF-1-direct- or -indirect-dependent manner, and highlighted the importance of caspase-1 in driving the sterile inflammatory response to CTX. Our data identify IRF-1 as important for the antitumor efficacy of CTX and for the regulation of many immunomodulatory activities of CTX, such as Th1 polarization, Treg depletion and inflammation.

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Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma

Abstract: The altered signalling molecules of PBL could represent biomarkers of impaired cytotoxic and immunoregulatory function of these cells, indicating melanoma-associated immunosuppression that facilitates tumour progression.

Cited by 15 publications

References 36 publications

IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the Ras-Rac1 pathway

IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the Ras-Rac1 pathway

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide

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