Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Guo, Huibin; Li, Ruifeng; Wang, Ming; Hou, Yingping; Liu, Shuoshuo; Peng, Ting; Zhao, Xiang-Yu; Lu, Liming; Han, Yali; Shao, Yiming; Chang, Ying‐Jun; Li, Cheng; Huang, Xiao‐Jun

doi:10.1002/advs.202200978

Cited by 7 publications

(5 citation statements)

References 74 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are in line with the previous findings showing that the phosphorylation of Stat3 was elevated in splenic T cells of Socs1 -deficient mice relative to those of wild-type mice ( 36 ). Downregulation of Socs1 in rat hepatocytes activates Jak2-Stat3 in an animal model of sepsis ( 37 ).…”

Section: Discussionsupporting

confidence: 93%

In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1

et al. 2022

View full text Add to dashboard Cite

IntroductionMycosis fungoides (MF), the most common type of Cutaneous T cell Lymphoma (CTCL), is characterized by an inflamed skin intermixed with proliferating malignant mature skin-homing CD4+ T cells. Detailed genomic analyses of MF skin biopsies revealed several candidate genes possibly involved in genesis of these tumors and/or potential targets for therapy. These studies showed, in addition to common loss of cell cycle regulator CDKN2A, activation of several oncogenic pathways, most prominently and consistently involving JAK/STAT signaling. SOCS1, an endogenous inhibitor of the JAK/STAT signaling pathway, was identified as a recurrently deleted gene in MF, already occurring in the earliest stages of the disease.MethodsTo explore the mechanisms of MF, we create in vivo mouse models of autochthonous CTCLs and these genetically engineered mouse models (GEMMS) can also serve as valid experimental models for targeted therapy. We describe the impact of allelic deletion of Socs1 in CD4 T cells of the skin. To achieve this, we crossed inducible Cre-transgenic mice in the CD4 lineage with transgenic mice carrying floxed genes of Socs1. We first determined optimal conditions for Socs1 ablation with limited effects on circulating CD4 T-cells in blood. Next, we started time-course experiments mimicking sustained inflammation, typical in CTCL. FACS analysis of the blood was done every week. Skin biopsies were analyzed by immunocytochemical staining at the end of the experiment.ResultsWe found that the Socs1 knockout transgenic group had thicker epidermis of treated skin compared with the control group and had more CD3 and CD4 in the skin of the transgenic group compared to the control group. We also noted more activation of Stat3 by staining for P-Stat3 in Socs1 knockout compared to wt CD4+T cells in the skin. The results also indicated that single copy loss of Socs1 in combination with sustained inflammation is insufficient to start a phenotype resembling early stage mycosis fungoides within eight weeks in these mice.ConclusionIn sum, we developed and optimized an autochthonous murine model permitting selective knockout of Socs1 in skin infiltrating CD4 T-cells. This paves the way for more elaborate experiments to gain insight in the oncogenesis of CTCL.

show abstract

Section: Discussionsupporting

confidence: 93%

In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Additionally, SOCS1 was identi ed as a negative regulator of PD-L1 through a barcoding system [31]. Moreover, SOCS1 has been characterized as an intracellular negative checkpoint for CD4 + T cells, and its inactivation restored proliferation suppression and anticancer e cacy in both murine and human CD4 + T cells [32,33]. Surprisingly, we observed a positive correlation between SOCS1 expression and the in ltration of activated CD4 + memory T cells and resting NK cells in TNBC, as well as PD-1 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of Triple-Negative Breast Cancer Subtypes Based on Ferroptosis- Related Gene Signature for Targeted Treatment Prioritization

Chen,

Huang,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

Ferroptosis, an iron-dependent form of programmed cell death, plays a crucial role in cancer therapies. However, its impact on chemotherapy, immune checkpoint inhibitor (ICI) treatments, and molecular subtypes of triple-negative breast cancer (TNBC) is poorly understood. In this study, we utilized the FUSCC TNBC cohort to classify TNBC patients into distinct subtypes based on the expression of eight ferroptosis-related genes (FRGs). We employed Gene Ontology (GO) and Gene Set Variation Analysis (GSVA) to characterize the immune phenotype and enriched pathways associated with these subtypes. Additionally, we developed the FerrScore model to identify potential compounds and predict the benefits of ICIs in TNBC patients. Our analysis revealed two ferroptosis-related subtypes with contrasting overall survival (OS) outcomes. Cluster 1 had superior OS and exhibited a "hot" tumor phenotype with increased immune cell infiltration and elevated expression of immune checkpoints compared to Cluster 2. We identified Everolimus as the most promising candidate drug for TNBC patients with a high FerrScore, considering CMap score, experimental evidence, and clinical trial status. Moreover, we validated FerrScore as a powerful metric for predicting the benefits of various ICIs. These findings highlight the influence of ferroptosis on the tumor microenvironment, enabling the classification of TNBC patients into subgroups with different OS outcomes. The FerrScore model has potential in screening compounds and predicting the benefits of ICIs in TNBC, offering valuable insights for treatment prioritization in clinical settings.

show abstract

“…Suppressor of cytokine signaling 1 (SOCS1) serves as a critical negative regulator for various inflammatory cytokines. It functions as the most potent member of the SOCS family, exerting negative regulation on the JAK/STAT pathway, and plays a crucial role in suppressing the secretion of proinflammatory cytokines such as interferon-γ (IFN-𝛾) [ 30 ]. The JAK/STAT signaling pathway is primarily regulated by cytokines and serves as a key regulator of innate immunity and the modulation of adaptive immune mechanisms.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-155 targets SOCS1 to inhibit osteoclast differentiation during orthodontic tooth movement

Jiao,

Mi,

et al. 2023

BMC Oral Health

View full text Add to dashboard Cite

Background MicroRNA-155 (miR-155) is a multifunctional miRNA whose expression is known to be involved in a range of physiological and pathological processes. Its association with several oral diseases has been established. However, the specific role of miR-155 in orthodontic tooth movement remains unclear. In this study, we investigated the impact of miR-155 on osteoclast differentiation and orthodontic tooth movement models, aiming to explore the underlying mechanisms. Methods In this experiment, we utilized various agents including miR-155 mimic, miR-155 inhibitor, as well as non-specific sequences (NC mimic & NC inhibitor) to treat murine BMMNCs. Subsequently, osteoclast induction (OC) was carried out to examine the changes in the differentiation ability of monocytes under different conditions. To assess these changes, we employed RT-PCR, Western blotting, and TRAP staining techniques. For the orthodontic tooth movement model in mice, the subjects were divided into two groups: the NaCl group (injected with saline solution) and the miR-155 inhibitor group (injected with AntagomiR-155). We observed the impact of orthodontic tooth movement using stereoscopic microscopy, micro-CT, and HE staining. Furthermore, we performed RT-PCR and Western blotting analyses on the tissues surrounding the moving teeth. Additionally, we employed TargetScan to predict potential target genes of miR-155. Results During osteoclast induction of BMMNCs, the expression of miR-155 exhibited an inverse correlation with osteoclast-related markers. Overexpression of miR-155 led to a decrease in osteoclast-related indexes, whereas underexpression of miR-155 increased those indexes. In the mouse orthodontic tooth movement model, the rate of tooth movement was enhanced following injection of the miR-155 inhibitor, leading to heightened osteoclast activity. TargetScan analysis identified SOCS1 as a target gene of miR-155. Conclusions Our results suggest that miR-155 functions as an inhibitor of osteoclast differentiation, and it appears to regulate osteoclasts during orthodontic tooth movement. The regulatory mechanism of miR-155 in this process involves the targeting of SOCS1.

show abstract

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Cited by 7 publications

References 74 publications

In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1

In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1

Identification of Triple-Negative Breast Cancer Subtypes Based on Ferroptosis- Related Gene Signature for Targeted Treatment Prioritization

MicroRNA-155 targets SOCS1 to inhibit osteoclast differentiation during orthodontic tooth movement

Contact Info

Product

Resources

About