scholarly journals The Relevance of SOCS1 Methylation and Epigenetic Therapy in Diverse Cell Populations of Hepatocellular Carcinoma

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1825
Author(s):  
Loraine Kay D. Cabral ◽  
Peter Andrew C. Reyes ◽  
Lory S. Crocè ◽  
Claudio Tiribelli ◽  
Caecilia H. C. Sukowati
Keyword(s):  
Hepatocellular Carcinoma ◽  
Suppressor Gene ◽  
Cellular Heterogeneity ◽  
Epigenetic Therapy ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Toxic Concentration ◽  
In Vitro Treatment ◽  
Demethylation Agent

The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy.

scholarly journals Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jatin Sharma ◽  
Teresa D. Collins ◽  
Tracoyia Roach ◽  
Shiwangi Mishra ◽  
Brandon K. Lam ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Lymphocyte Activation ◽  
Signal Propagation ◽  
Skin Lesions ◽  
Effector Memory ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Autoantibody Production ◽  
Ifn Γ

AbstractAutoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

scholarly journals Hypermethylation of Suppressor of Cytokine Signaling 1 in Hepatocellular Carcinoma Patients

2012 ◽  
Vol 13 (7) ◽  
pp. 3489-3493 ◽  
Author(s):  
Pensri Saelee ◽  
Ubol Chuensumran ◽  
Sopit Wongkham ◽  
Sunanta Chariyalertsak ◽  
Danai Tiwawech ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling

scholarly journals Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network

2020 ◽  
Author(s):  
Miriam Pagin ◽  
Simone Giubbolini ◽  
Cristiana Barone ◽  
Gaia Sambruni ◽  
Yanfen Zhu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Signaling ◽  
Normal Brain ◽  
Suppressor Of Cytokine Signaling ◽  
Self Renewal ◽  
Upstream Regulator ◽  
Socs3 Expression ◽  
Pharmacological Manipulations

AbstractThe Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSC). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, individually or in combination, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2). Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Further, Fos requirement for efficient long-term proliferation was demonstrated by the strong reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Suppressor of cytokine signaling 3 (Socs3) gene is strongly downregulated following Sox2 deletion, and its reexpression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 reexpression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, as well as results from the literature, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; in turn, Fos, Jun and Egr2 may activate Socs3. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.Significance statementProliferation and maintenance of NSC are essential during normal brain development, and, postnatally, for the maintenance of hippocampal function and memory until advanced age. Little is known about the molecular mechanisms that maintain the critical aspects of NSC biology (quiescence and proliferation) in postnatal age. Our work provides a methodology, transduction of genes deregulated following Sox2 deletion, that allows to test many candidate genes for their ability to sustain NSC proliferation. In principle, this may have interesting implications for identifying targets for pharmacological manipulations.

scholarly journals Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

2017 ◽  
Vol 37 (9) ◽  
Author(s):  
Raquel Sánchez-Díaz ◽  
Rafael Blanco-Dominguez ◽  
Sandra Lasarte ◽  
Katerina Tsilingiri ◽  
Enrique Martín-Gayo ◽  
...  
Keyword(s):  
Treg Cell ◽  
Feedback Loop ◽  
Cell Development ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Hairpin Rna ◽  
Lectin Receptor ◽  
Reporter Mice ◽  
Itreg Cell

ABSTRACT Thymus-derived regulatory T (tTreg) cells are key to preventing autoimmune diseases, but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg cell homeostasis through the regulation of BIC/microRNA 155 (miR-155) and its target, suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69 +/− or Foxp3-mRFP/cd69 −/− reporter mice and short hairpin RNA (shRNA)-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3+ cells. This results in BIC/miR-155 inhibition, increased SOCS-1 expression, and severely impaired tTreg cell development in embryos, adults, and Rag2−/− γc−/− hematopoietic chimeras reconstituted with cd69 −/− stem cells. Accordingly, mirn155 −/− mice have an impaired development of CD69+ tTreg cells and overexpression of the miR-155-induced CD69 pathway, suggesting that both molecules might be concomitantly activated in a positive-feedback loop. Moreover, in vitro-inducible CD25+ Treg (iTreg) cell development is inhibited in Il2rγ−/−/cd69 −/− mice. Our data highlight the contribution of CD69 as a nonredundant key regulator of BIC/miR-155-dependent Treg cell development and homeostasis.

scholarly journals Epigenetic down-regulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats

Cell Cycle ◽  
2008 ◽  
Vol 7 (20) ◽  
pp. 3202-3210 ◽  
Author(s):  
Tetyana V. Bagnyukova ◽  
Volodymyr P. Tryndyak ◽  
Levan Muskhelishvili ◽  
Sharon A. Ross ◽  
Frederick A. Beland ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Down Regulation

Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth

2006 ◽  
Vol 291 (5) ◽  
pp. R1399-R1405 ◽  
Author(s):  
S. Gentili ◽  
J. S. Schwartz ◽  
M. J. Waters ◽  
I. C. McMillen
Keyword(s):  
Adrenal Gland ◽  
Mrna Expression ◽  
Tissue Growth ◽  
Late Gestation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Subsequent Increase ◽  
Fetal Sheep

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90–120 days) before the prepartum activation, which occurs around 135 days gestation (term = 147 ± 3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease ( P < 0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression ( P < 0.05). Similarly, there was an increase ( P < 0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

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