The Role of JAK-STAT-SOCS1 Axis in Tumorigenesis, Malignant Progression and Lymphatic Metastasis of Penile Cancer.

Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

The impact of miRNA-155 in acute and chronic toxoplasmosis in Iraqi women.

Toxoplasmosis is a prevalent parasitic infection caused by Toxoplasma gondii known to induce complex immune responses, to control the infection. MicroRNAs (miRNAs) are a cluster of small noncoding RNAs that are reported to have regulatory functions in the immune response. The objective of this study is to assess the expression of miR-155 and its targets, Src homology-2 domain-containing inositol 5- phosphatase 1 (SHIP-1) and suppressor of cytokine signaling-1 (SOCS1), in non-pregnant Iraqi women seropositive for toxoplasmosis. The study included 55 non-pregnant women positive for toxoplasmosis (20 in the acute phase and 35 in the chronic phase) and 35 non-pregnant women negative for toxoplasmosis (control group). Serum samples were collected from all participants to investigate the expression of miR-155 by RT‒PCR, in addition to the levels of SOCS1 and SHIP-1 measured by ELISA. The results showed a significant increase in the expression of miR-155 in both groups of acute and chronic toxoplasmosis compared to the control group. Lower levels of SOCS1 and SHIP-1 were found in acutely infected women compared to those with chronic infection and non-infected women. These findings showed the possible critical impact of miR-155 on host immune response during T.gondii infection, proposing that miR-155 can be explored as a prospective target to support host immune response against infectious diseases, with special help in early detection and management of toxoplasmosis in high-risk immunocompromised patients. Further studies are needed to evaluate the molecular pathways by which miRNAs improve immunity against toxoplasmosis.

Downregulation of lncRNA CDKN2B-AS1 attenuates inflammatory response in mice with allergic rhinitis by regulating miR-98-5p/SOCS1 axis.

Long non-coding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in various diseases has been verified. However, the underlying mechanism of CDKN2B-AS1 contributes to the development of allergic rhinitis (AR) remains unknown. To evaluate the impact of CDKN2B-AS1 on AR, BALB/c mice were sensitized by intraperitoneal injection of normal saline containing ovalbumin (OVA) and calmogastrin to establish an AR model. Nasal rubbing and sneezing were documented after the final OVA treatment. The concentrations of IgE, IgG1, and inflammatory elements were quantified using ELISA. Hematoxylin and eosin (H&E) staining and immunofluorescence were used to assess histopathological variations and tryptase expression, respectively. StarBase, TargetScan and luciferase reporter assays were applied to predict and confirm the interactions among CDKN2B-AS1, miR-98-5p, and SOCS1. CDKN2B-AS1, miR-98-5p, and SOCS1 levels were assessed by quantitative real-time PCR (qRT-PCR) or western blotting. Our results revealed that CDKN2B-AS1 was obviously over-expressed in the nasal mucosa of AR patients and AR mice. Down-regulation of CDKN2B-AS1 significantly decreased nasal rubbing and sneezing frequencies, IgE and IgG1 concentrations, and cytokine levels. Furthermore, down-regulation of CDKN2B-AS1 also relieved the pathological changes in the nasal mucosa, and the infiltration of eosinophils and mast cells. Importantly, these results were reversed by the miR-98-5p inhibitor, whereas miR-98-5p directly targeted CDKN2B-AS1, and miR-98-5p negatively regulated SOCS1 level. Our findings demonstrate that down-regulation of CDKN2B-AS1 improves allergic inflammation and symptoms in a murine model of AR through the miR-98-5p/SOCS1 axis, which provides new insights into the latent functions of CDKN2B-AS1 in AR treatment.

IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11.

Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.

SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity.

Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.

Effects of extracellular vesicles from adipose-derived stem cells on human keloid fibroblasts via the SOCS1/JAK2/STAT3 pathway.

BACKGROUND: Keloid represents a benign skin tumor with many cancer-like features. Extracellular vesicles (EVs) derived from human adipose-derived stem cells (hADSCs) play a role in cell migration of multiple diseases. AIMS: This study aimed to investigate the impact of hADSC-EVs on human keloid fibroblasts (HKFs). METHODS: hADSCs were cultured to the 3rd generation, and subsequently assessed for their osteogenic, adipogenic, and chondrogenic differentiative abilities using flow cytometry, alizarin red, oil red O, and alcian blue staining techniques. hADSC-EVs were isolated through ultracentrifugation and subsequently identified. HKFs at the 3rd generation were subjected to treatment with hADSC-EVs to observe their endocytosis of EVs by immunofluorescence. CCK-8, wound healing, and Transwell assays were performed to test HKF proliferation and migration. The levels of autophagy proteins, collagens, and Janus kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) were determined through Western blot analysis. Suppressor of cytokine signaling 1 (SOCS1) expression was determined by RT-qPCR and Western blot. RESULTS: hADSC-EVs were successfully isolated from hADSCs. PKH67-labeled hADSC-EVs were observed to be endocytosed by HKFs, resulting the inhibition of HKF proliferation, migration, as well as a reduction in collagen deposition. hADSC-EVs carried SOCS1 into HKFs to suppress HKF autophagy. SOCS1 downregulation in hADSC-EVs partially nullified the inhibitory effect of hADSC-EVs on HKFs. hADSC-EV-carried SOCS1 inhibited the activation of the JAK2/STAT3 pathway. JAK2/STAT3 pathway activation partially abrogated the suppression of hADSC-EVs on the proliferation, migration, and collagen deposition of HKF. CONCLUSION: hADSC-EVs carried SOCS1 into HKFs and suppressed HKF autophagy, proliferation, migration, and collagen deposition by inactivating the JAK2/STAT3 pathway.

LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer.

Tumor-associated macrophages (TAMs) mainly exhibit the characteristics of M2-type macrophages, and the regulation of TAM polarization is a new target for cancer therapy, among which lncRNAs are key regulatory molecules. This study aimed to explore the effects of lncRNA-HOXC-AS2 on non-small cell lung cancer (NSCLC) by regulating TAM polarization. THP-1 cells were used to differentiate into macrophages, and TAMs were obtained by coculture with A549 cells. The M1/M2 cell phenotype and HOXC-AS2 expression were detected, and A549-derived exosomes (A549-exo) were used to elucidate the effects of A549 on macrophage polarization and HOXC-AS2 expression. Then, by interfering with HOXC-AS2 or STAT1, the effects of HOXC-AS2 regulation of STAT1 on the TAM phenotype and STAT1/SOCS1 and STAT1/CIITA pathways were analyzed, and the proliferation and metastasis of NSCLC cells in the coculture system were also detected. Results showed that HOXC-AS2 expression in M2 macrophages and TAMs was significantly higher than that in M1 macrophages, and A549-exo promoted HOXC-AS2 expression and M2 polarization. Intervention HOXC-AS2 resulted in increased M1 marker expression, decreased M2 marker expression, and activation of STAT1/SOCS1 and STAT1/CIITA pathways in TAMs. In addition, HOXC-AS2 was mainly expressed in the cytoplasm of TAMs and could bind to STAT1. Further experiments confirmed that intervention HOXC-AS2 promoted the M1 polarization of TAMs by targeting STAT1 and weakened the promoting effects of TAMs on the proliferation and metastasis of NSCLC. In conclusion, HOXC-AS2 inhibited the activation of STAT1/SOCS1 and STAT1/CIITA pathways and promoted M2 polarization of TAMs by binding with STAT1, thus promoting NSCLC.

EP300 improves endothelial injury and mitochondrial dysfunction in coronary artery disease by regulating histone acetylation of SOCS1 promoter via inhibiting JAK/STAT pathway.

Endothelial cell injury and mitochondrial dysfunction are crucial events during coronary artery disease (CAD). Suppressor of cytokine signaling-1 (SOCS1) is a negative mediator for inflammation, but there are few reports regarding histone acetylation of SOCS1 in CAD. The aim of the current study is to examine the impact of SOCS1 in CAD patients and human umbilical vein endothelial cells (HUVECs). We enrolled patients with CAD and healthy volunteers. HUVECs treated with ox-LDL were used as in vitro model. This study showed that SOCS1 expression was decreased in patients with CAD and ox-LDL-stimulated HUVECs. Overexpressing SOCS1 ameliorated endothelial cell injury and mitochondrial dysfunction induced by ox-LDL in vitro. Moreover, EP300 promoted SOCS1 transcription through increasing the acetylation of SOCS1 and recruiting H3K27ac to the SOCS1 gene promoter in HUVECs induced by ox-LDL. Additionally, SOCS1 repressed JAK/STAT cascade in ox-LDL-stimulated HUVECs. Silencing of EP300 reversed endothelial cell injury and mitochondrial dysfunction ameliorated by overexpression of SOCS1 in ox-LDL-induced HUVECs. In summary, SOCS1 alleviated endothelial injury and mitochondrial dysfunction via enhancing H3K27ac acetylation by recruiting EP300 to promoter region and inhibiting JAK/STAT pathway. These results contribute to discover underlying diagnostic biomarkers and therapeutic targets for CAD.

NaAsO2 regulates TLR4/MyD88/NF-κB signaling pathway through DNMT1/SOCS1 to cause apoptosis and inflammation in hepatic BRL-3A cells.

The exact molecular mechanism of arsenic-induced liver injury has not been fully elucidated. The aim of the study was to investigate the potential mechanism of NaAsO2-induced cytotoxicity in BRL-3A cells and to provide a basis for the mechanism of arsenic poisoning. BRL-3A cells were treated with different doses of NaAsO2, DNMT1 inhibitor (DC_517), TLR4 inhibitor (TAK-242), and transfection of SOCS1 plasmid. Cell activity, apoptosis, inflammation and protein expression of DNMT1, SOCS1, TLR4, MyD88, and NF-κB were detected by CCK8 assay, Annexin V-FITC and Western blot, respectively. With increasing NaAsO2 doses, BAX and caspase-3 expression increased, Bcl-2 expression decreased, pro-inflammatory factors TNF-α, IL-1ß, and IL-6 increased, and cell activity decreased causing increased apoptosis. When BRL-3A was intervened with 10, and 20 µmol/L NaAsO2, DNMT1 expression was elevated, SOCS1 expression was decreased, and TLR4, MyD88, p-IκBα/IκBα, and p-p65/p65 expression were elevated. After the combination of NaAsO2 and DC_517, compared to the NaAsO2 group, apoptosis and inflammation were attenuated, SOCS1 expression was elevated and TLR4, MyD88, p-IκBα/IκBα and p-p65/p65 expression was decreased. Apoptosis and inflammation were attenuated after co-treatment of SOCS1 high expression with NaAsO2 compared to the NaAsO2 group. In addition, TLR4, MyD88, p-IκBα/IκBα and p-p65/p65 expression was reduced. When NaAsO2 and TAK-242 were combined, apoptosis and inflammation were attenuated. Besides MyD88, p-IκBα/IκBα and p-p65/p65 expression was reduced compared to the NaAsO2 group. We found that NaAsO2 induce apoptosis and inflammation in BLR-3A cells, which may be related to inhibit SOCS1 through regulation of DNMT1 and thus activating the TLR4/MyD88/NF-κB signaling pathway.

Urinary stem cell-derived exocrine circRNA ATG7 regulates the SOCS1/STAT3 signaling pathway through miR-4500, inhibits M1 macrophage polarization, and alleviates the progression of diabetes nephropathy.

OBJECTIVE: The etiopathogenesis of diabetes nephropathy (DN) has not yet been fully clarified. Finding effective treatments to prevent renal failure in DN patients has become the main focus of research in recent years. Circular RNA (circRNA) has been shown to play a momentous role in DN progression. Based on this, we aimed to investigate the potential mechanism by which urine-derived stem cell (USC)-derived exosome circRNA ATG7 (Exo-ATG7) mediates DN progression. METHODS: Exosomes from USCs were isolated and identified. The DN rat model was established by intraperitoneally injecting 60 mg/kg streptozotocin. The protein expression levels were measured by Western blot and immunofluorescence. HE and Masson staining were used to evaluate renal injury, and the expression of related genes was detected by RT-qPCR. RESULTS: CircRNA ATG7 was significantly downregulated in the DN rat model, and the extracellular vesicles of USCs improved renal function and reduced inflammation in DN rats. However, after knocking down the USCs-derived exosome circRNA ATG7, improvement and therapeutic effect on renal function in DN rats were lost. In addition, overexpression of ATG7 facilitated the switching of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype both in vivo and in vitro. Mechanistically, upregulation of circRNA ATG7 expression can alleviate renal damage in DN rats. Importantly, the USCs-derived exosome circRNA ATG7 promotes macrophage M2 polarization by regulating the SOCS1/STAT3 signaling pathway through miR-4500. In addition, animal experiments also confirmed that after knocking down ATG7 in USC cells, the extracted exosome-treated DN rats could weaken the therapeutic effect of USC exosomes. CONCLUSION: Our research results indicate that USC-derived exosomal circRNA ATG7 facilitates macrophage phenotype switching from M1 to M2 through the SOCS1/STAT3 signaling pathway mediated by miR-4500, thereby inhibiting DN progression.

Transcriptional regulation of suppressors of cytokine signaling during infection with Mycobacterium tuberculosis in human THP-1-derived macrophages and in mice.

Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPß to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival.

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

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.

Disparate viral pandemics from COVID19 to monkeypox and beyond: a simple, effective and universal therapeutic approach hiding in plain sight.

The field of antiviral therapeutics is fixated on COVID19 and rightly so as the fatalities at the height of the pandemic in the United States were almost 1,000,000 in a twelve month period spanning parts of 2020/2021. A coronavirus called SARS-CoV2 is the causative virus. Development of a vaccine through molecular biology approaches with mRNA as the inducer of virus spike protein has played a major role in driving down mortality and morbidity. Antivirals have been of marginal value in established infections at the level of hospitalization. Thus, the current focus is on early symptomatic infection of about the first five days. The Pfizer drug paxlovid which is composed of nirmatrelvir, a peptidomimetic protease inhibitor of SARS-CoV2 Mpro enzyme, and ritonavir to retard degradation of nirmatrelvir, is the current FDA recommended treatment of early COVID19. There is no evidence of broad antiviral activity of paxlovid against other diverse viruses such as the influenza virus, poxviruses, as well as a host of respiratory viruses. Although type I interferons (IFNs) are effective against SARS-CoV2 in cell cultures and in early COVID19 infections, they have not been broadly recommended as therapeutics for COVID19. We have developed stable peptidomimetics of both types I and II IFNs based on our noncanonical model of IFN signaling involving the C-terminus of the IFNs. We have also identified two members of intracellular checkpoint inhibitors called suppressors of cytokine signaling (SOCS), SOCS1 and SOCS3 (SOCS1/3), and shown that they are virus induced intrinsic virulence proteins with activity against IFN signaling enzymes JAK2 and TYK2. We developed a peptidomimetic antagonist, based on JAK2 activation loop, against SOCS1/3 and showed that it synergizes with the IFN mimetics for potent broad spectrum antiviral activity without the toxicity of intact IFN molecules. IFN mimetics and the SOCS1/3 antagonist should have an advantage over currently used antivirals in terms of safety and potency against a broad spectrum of viruses.

IL4Rα and IL17A Blockade Rescue Autoinflammation in SOCS1 Haploinsufficiency.

By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.

Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens.

Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors. A comprehensive CRISPR tiling screen of the SOCS1-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.

Synthetic High-Density Lipoprotein-Based Nanomedicine to Silence SOCS1 in Tumor Microenvironment and Trigger Antitumor Immunity against Glioma.

Immunotherapies have shed light on the treatment of many cancers, but have not improved the outcomes of glioma (GBM). Here, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) was associated with the GBM-associated immunosuppression and developed a multifunctional nanomedicine, which silenced SOCS1 in the tumor microenvironment (TME) of GBM and triggered strong antitumor immunity against GBM. Synthetic high-density lipoprotein (sHDL) was selected as the nanocarrier and a peptide was used to facilitate the blood-brain-barrier (BBB) penetration. The nanocarrier was loaded with a small interfering RNA (siRNA), a peptide, and an adjuvant to trigger antitumor immunity. The nanomedicine concentrated on the TME in vivo, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. Our work provides an alternative strategy to simultaneously target and modulate the TME in GBM patients and points to an avenue for enhancing the efficacy of immunotherapeutics.

Suppressor of Cytokine Signaling 1 Haploinsufficiency: A New Driver of Autoimmunity and Immunodysregulation.

Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling that inhibits the activation of Janus kinases. A human disease caused by SOCS1 haploinsufficiency was first identified in 2020. To date, 18 cases of SOCS1 haploinsufficiency have been described. These patients experience enhanced activation of leukocytes and multiorgan system immunodysregulation, with immune-mediated cytopenia as the most common feature. In this review, the authors provide an overview on the biology of SOCS1 and summarize their knowledge of SOCS1 haploinsufficiency including genetics and clinical manifestations. They discuss the available treatment experience and outline an approach for the evaluation of suspected cases.

Gold nanoparticles attenuate the interferon-γ induced SOCS1 expression and activation of NF-κB p65/50 activity via modulation of microRNA-155-5p in triple-negative breast cancer cells.

Objective: Triple-negative breast cancer (TNBC) is a very aggressive form of cancer that grows and spreads very fast and generally relapses. Therapeutic options of TNBC are limited and still need to be explored completely. Gold nanoparticles conjugated with citrate (citrate-AuNPs) are reported to have anticancer potential; however, their role in regulating microRNAs (miRNAs) in TNBC has never been investigated. This study investigated the potential of citrate-AuNPs against tumorigenic inflammation via modulation of miRNAs in TNBC cells. Methods: Gold nanoparticles were chemically synthesized using the trisodium-citrate method and were characterized by UV-Vis spectrophotometry and dynamic light scattering studies. Targetscan bioinformatics was used to analyze miRNA target genes. Levels of miRNA and mRNA were quantified using TaqMan assays. The pairing of miRNA in 3'untranslated region (3'UTR) of mRNA was validated by luciferase reporter clone, containing the entire 3'UTR of mRNA, and findings were further re-validated via transfection with miRNA inhibitors. Results: Newly synthesized citrate-AuNPs were highly stable, with a mean size was 28.3 nm. The data determined that hsa-miR155-5p is a direct regulator of SOCS1 (suppressor-of-cytokine-signaling) expression and citrate-AuNPs inhibits SOCS1 mRNA/protein expression via modulating hsa-miR155-5p expression. Transfection of TNBC MDA-MB-231 cells with anti-miR155-5p markedly increased SOCS1 expression (p<0.001), while citrate-AuNPs treatment significantly inhibited anti-miR155-5p transfection-induced SOCS1 expression (p<0.05). These findings were validated by IFN-γ-stimulated MDA-MB-231 cells. Moreover, the data also determined that citrate-AuNPs also inhibit IFN-γ-induced NF-κB p65/p50 activation in MDA-MB-231 cells transfected with anti-hsa-miR155-5p. Conclusion: Newly generated citrate-AuNPs were stable and non-toxic to TNBC cells. Citrate-AuNPs inhibit IFN-γ-induced SOCS1 mRNA/protein expression and deactivate NF-κB p65/50 activity via negative regulation of hsa-miR155-5p. These novel pharmacological actions of citrate-AuNPs on IFN-γ-stimulated TNBC cells provide insights that AuNPs inhibit IFN-γ induced inflammation in TNBC cells by modulating the expression of microRNAs.

SOCS1 acts as a ferroptosis driver to inhibit the progression and chemotherapy resistance of triple-negative breast cancer.

OBJECTIVES: Ferroptosis is involved in many types of cancers, including triple-negative breast cancer (TNBC). Suppressor of cytokine signaling 1 (SOCS1) has recently been implicated as a regulator of ferroptosis. We aim to explore whether targeting SOCS1 is a potential therapeutic strategy for TNBC therapy. METHODS: Stable cell lines were constructed using lentivirus transfection. Cell viability was determined using CCK-8 and cell colony formation assays, respectively. Assays including lactate dehydrogenase release, lipid peroxidation and malondialdehyde assays were conducted to evaluate ferroptosis. Real-time quantitative polymerase chain reaction and western blotting were performed to evaluate mRNA and protein expression, respectively. A xenograft animal model was established by subcutaneous injection of cells into the flank. RESULTS: Our results showed that SOCS1 overexpression inhibited cell proliferation and induced ferroptosis in TNBC cells, while SOCS1 knockdown promoted cell proliferation and reduced ferroptosis. We also found that SOCS1 regulated ferroptosis by modulating GPX4 expression. Furthermore, SOCS1 regulated cisplatin resistance in TNBC cells by promoting ferroptosis. Our in vivo data suggested that SOCS1 regulated tumor growth and cisplatin resistance in vivo. CONCLUSIONS: SOCS1 inhibits the progression and chemotherapy resistance of TNBC by regulating GPX4 expression.