Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment

Jiang, Mengmeng; Zhang, Wenwen; Liu, Pengpeng; Yu, Wenwen; Liu, Ting; Yu, Jinpu

doi:10.3389/fimmu.2017.00070

Cited by 80 publications

(75 citation statements)

References 104 publications

(123 reference statements)

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“…Among the top scoring GBM-specific essential genes was Suppressor of Cytokine Signaling 3 (SOCS3), which has been previously shown to maintain stemness in neural stem cells (Cao et al, 2006). Intriguingly, SOCS3 was reported to have opposing effects in glioma and function as either a tumor suppressor or oncogene depending on context (Jiang et al, 2017;Martini et al, 2008;Zhou et al, 2007). To gain a better understanding of the functional mechanisms underlying SOCS3 in GSCs, we first knocked out its expression with 2 individual gRNAs to validate its essentiality in multiple GSC cultures.…”

Section: Genetic Programs Governing Stemness Are Essential In Gsc Culmentioning

confidence: 99%

The functional genomic circuitry of human glioblastoma stem cells

MacLeod

Bozek

Rajakulendran

et al. 2018

Preprint

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SummarySuccessful glioblastoma (GBM) therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells to interrogate function of the coding genome, we identify diverse actionable pathways responsible for growth that reveal the gene-essential circuitry of GBM stemness. In particular, we describe the Sox developmental transcription factor family; H3K79 methylation by DOT1L; and ufmylation stress responsiveness programs as essential for GBM stemness. Additionally, we find mechanisms of temozolomide resistance and sensitivity that could lead to combination strategies with this standard of care treatment. By reaching beyond static genome analysis of bulk tumors, with a genome wide functional approach, we dive deep into a broad range of biological processes to provide new understanding of GBM growth and treatment resistance.SignificanceGlioblastoma (GBM) remains an incurable disease despite an increasingly thorough depth of knowledge of the genomic and epigenomic alterations of bulk tumors. Evidence from multiple approaches support that GBM reflects an aberrant developmental hierarchy, with GBM stem cells (GSCs), fueling tumor growth and invasion. The properties of this tumor subpopulation may also in part explain treatment resistance and disease recurrence. Unfortunately, we still have a limited knowledge of the molecular circuitry of these cells and progress has been slow as we have not been able, until recently, to interrogate function at the genome-wide scale. Here, using parallel genome-wide CRISPR-Cas9 screens, we identify the essential genes for GSC growth. Further, by screening in the presence of low and high dose temozolomide, we identify mechanisms of drug resistance and sensitivity. These functional screens in patient derived cells reveal new aspects of GBM biology and identify a diversity of actionable targets such as genes governing stem cell traits, epigenome regulation and the response to stress stimuli.

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Section: Genetic Programs Governing Stemness Are Essential In Gsc Culmentioning

confidence: 99%

The functional genomic circuitry of human glioblastoma stem cells

MacLeod

Bozek

Rajakulendran

et al. 2018

Preprint

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“…However, the inhibitory effect of IL-6 signaling seemed not related to SOCS3 induction in NCI-H69 cells because: i) pre-stimulation with sIL-6R/IL-6 followed by removal shortly before IL-27 stimulation failed to interfere with HLA class I induction, ii) SOCS3 is constitutively expressed by NCI-H69 cells and is not further induced by sIL-6R/IL-6 and iii) IL-27 induces STAT1 signaling also in the presence of sIL-6R/IL-6. The role of SOCS3 in cancer is still controversial, because SOCS3 has been reported as a tumor-suppressor or tumor-promoting molecule, in different tumors [44]. For example, in pancreatic cancer SOCS3 expression correlates with a better prognosis and overexpression of SOCS3 limits tumor growth, while SOCS3 silencing by promoter methylation has opposite effects [45].…”

Section: Discussionmentioning

confidence: 99%

IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

Carbotti

Nikpoor

Vacca

et al. 2017

J Exp Clin Cancer Res

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BackgroundRecently, immunotherapy with anti-PD-1 antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC). Since anti-PD-1 re-activates anti-tumor Cytotoxic T Lymphocyte (CTL) responses, it is crucial to understand the mechanisms regulating HLA class I, and PD-L1 expression in HLA-negative SCLC. Here we addressed the role of IL-27, a cytokine related to both IL-6 and IL-12 families.MethodsThe human SCLC cell lines NCI-N592, -H69, -H146, -H446 and -H82 were treated in vitro with different cytokines (IL-27, IFN-γ, IL-6 or a soluble IL-6R/IL-6 chimera [sIL-6R/IL-6]) at different time points and analyzed for tyrosine-phosphorylated STAT proteins by Western blot, for surface molecule expression by immunofluorescence and FACS analyses or for specific mRNA expression by QRT-PCR. Relative quantification of mRNAs was calculated by the ΔΔCT method. The Student’s T test was used for the statistical analysis of experimental replicates.ResultsIL-27 triggered STAT1/3 phosphorylation and up-regulated the expression of surface HLA class I antigen and of TAP1 and TAP2 mRNA in four out of five SCLC cell lines tested. The IL-27-resistant NCI-H146 cells showed up-regulation of HLA class I by IFN-γ. IFN-γ also induced expression of PD-L1 in SCLC cells, while IL-27 was less potent in this respect. IL-27 failed to activate STAT1/3 phosphorylation in NCI-H146 cells, which display a low expression of the IL-27RA and GP130 receptor chains. As GP130 is shared in IL-27R and IL-6R complexes, we assessed its functionality in response to sIL-6R/IL-6. sIL-6R/IL-6 failed to trigger STAT1/3 signaling in NCI-H146 cells, suggesting low GP130 expression or uncoupling from signal transduction. Although both sIL-6R/IL-6 and IL-27 triggered STAT1/3 phosphorylation, sIL-6R/IL-6 failed to up-regulate HLA class I expression, in relationship to the weak activation of STAT1. Finally sIL-6R/IL-6 limited IL-27-effects, particularly in NCI-H69 cells, in a SOCS3-independent manner, but did not modify IFN-γ induced HLA class I up-regulation.ConclusionsIn conclusion, IL-27 is a potentially interesting cytokine for restoring HLA class I expression for SCLC combined immunotherapy purposes. However, the concomitant activation of the IL-6 pathway may limit the IL-27 effect on HLA class I induction but did not significantly alter the responsiveness to IFN-γ.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0608-z) contains supplementary material, which is available to authorized users.

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“…This system aims to protect organisms from permanent and/or overstimulation that could lead, for instance, to severe systemic inflammations mediated by IFN-γ signaling [182]. Conversely, a deficit in SOCS expression could play a pivotal role in the development and progression of cancers [183]. Expression of SOCS3, which has been shown to inhibit JAK1, JAK2, and TYK2 [184], is frequently reduced in cancer cells, thereby leading to a growth advantage.…”

Section: Hsf and Socs Regulationmentioning

confidence: 99%

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Hermetet

Girodon

Jego

2019

Cancers

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While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

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Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment

Cited by 80 publications

References 104 publications

The functional genomic circuitry of human glioblastoma stem cells

The functional genomic circuitry of human glioblastoma stem cells

IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

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