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Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-ß superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.
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The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
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Homeostasis , Inflamación , Neoplasias , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Neoplasias/inmunología , Neoplasias/terapia , Homeostasis/inmunología , Inflamación/inmunología , Animales , Transducción de Señal , Autoinmunidad , Citocinas/metabolismo , Citocinas/inmunologíaRESUMEN
Common variable immunodeficiency is a heterogeneous symptomatic group of inborn errors of immunity that mainly affects antibodies production and/or function, predisposing patients to recurrent and severe infections. More than half of them usually develop autoimmunity, lymphoproliferation, enteropathy, and malignancies. Among these conditions, chronic lung disease such as granulomatous-lymphocytic interstitial lung disease is one of the leading causes of death in these patients. Recently, many genes that play a key role in B and T cells' development, maintenance, and/or cytokines signaling pathways have been implicated in the pathogenesis of the disease. Here, we describe the first Argentinian patient presenting with common variable immunodeficiency and granulomatous-lymphocytic interstitial lung disease, harboring two in cis heterozygous variants in the SOCS1 gene.
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At present, the function of SOCS1 in Kashin-Beck disease (KBD) has not been reported. This study aims to explore the expression and mechanism of SOCS1 in KBD, and provide theoretical basis for the prevention and treatment of KBD. The expression of SOCS1 were measured by qRT-PCR and Western blot. ELISA was used to detect the content of SOCS1 in serum and synovial fluid. CCK-8 kits were selected to measure the cell viability. Methylation Specific PCR (MSP) assay is used to detect the methylation level of SOCS1 in chondrocytes. Flow cytometry was used to analyze the apoptosis rate of chondrocytes in different groups. The expression of apoptosis related proteins (caspase-3 and caspase-9) and Cytochrome c were detected using Western blot. The mitochondrial ROS, ATP and the activity of mitochondrial respiratory chain complexes were detected using commercial kits. The results showed that the expression of SOCS1 significantly increases in KBD patients and T-2 induced chondrocytes. Further research has found that the methylation levels of SOCS1 were significantly reduced in KBD patients and T-2 induced chondrocytes. Functional studies have found that SOCS1 silencing inhibited chondrocyte apoptosis and mitochondrial dysfunction. More importantly, SOCS1 regulated mitochondrial mediated chondrocyte apoptosis through the IGF-1/IGF-1R/FAK/Drp1 pathway. In conclusion, SOCS1 expression is increased and methylation levels are decreased in KBD, and is involved in regulating mitochondrial mediated apoptosis in T-2 induced chondrocytes through IGF-1/IGF-1R/FAK/Drp1 signaling. This study provides new theoretical basis for the treatment and prevention of KBD in clinical practice.
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Apoptosis , Condrocitos , Metilación de ADN , Mitocondrias , Regiones Promotoras Genéticas , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Apoptosis/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Condrocitos/metabolismo , Mitocondrias/metabolismo , Mitocondrias/genética , Regiones Promotoras Genéticas/genética , Enfermedad de Kashin-Beck/metabolismo , Enfermedad de Kashin-Beck/genética , Enfermedad de Kashin-Beck/patología , Masculino , Persona de Mediana Edad , Femenino , Células Cultivadas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genéticaRESUMEN
BACKGROUND: Human liver cancer stem-like cells (HLCSLCs) are widely acknowledged as significant factors in the recurrence and eradication of hepatocellular carcinoma (HCC). The sustenance of HLCSLCs' stemness is hypothesized to be intricately linked to the epigenetic process of DNA methylation modification of genes associated with anticancer properties. The present study aimed to elucidate the stemness-maintaining mechanism of HLCSLCs and provide a novel idea for the clearance of HLCSLCs. METHODS: The clinical relevance of DNMT1 and SOCS1 in hepatocellular carcinoma (HCC) patients was evaluated through the GEO and TCGA databases. Cellular immunofluorescence assay, methylation-specific PCR, chromatin immunoprecipitation were conducted to explore the expression of DNMT1 and SOCS1 and the regulatory relationship between them in HLCSLCs. Spheroid formation, soft agar colony formation, expression of stemness-associated molecules, and tumorigenicity of xenograft in nude mice were used to evaluate the stemness of HLCSLCs. RESULTS: The current analysis revealed a significant upregulation of DNMT1 and downregulation of SOCS1 in HCC tumor tissues compared to adjacent normal liver tissues. Furthermore, patients exhibiting an elevated DNMT1 expression or a reduced SOCS1 expression had low survival. This study illustrated the pronounced expression and activity of DNMT1 in HLCSLCs, which effectively targeted the promoter region of SOCS1 and induced hypermethylation, consequently suppressing the expression of SOCS1. Notably, the stemness of HLCSLCs was reduced upon treatment with DNMT1 inhibitors in a concentration-dependent manner. Additionally, the overexpression of SOCS1 in HLCSLCs significantly mitigated their stemness. The knockdown of SOCS1 expression reversed the effect of DNMT1 inhibitor on the stemness of HLCSLCs. DNMT1 directly binds to the SOCS1 promoter. In vivo, DNMT1 inhibitors suppressed SOCS1 expression and inhibited the growth of xenograft. CONCLUSION: DNMT1 targets the promoter region of SOCS1, induces hypermethylation of its CpG islands, and silences its expression, thereby promoting the stemness of HLCSLCs.
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Cervical cancer (CC) is a malignant tumor primarily caused by the persistent infection with high-risk strains of human papillomavirus. This study investigates the aberrant expression of Tripartite Motif Containing 8 (TRIM8) in CC and its impact on cell proliferation, invasion, and migration. Expression levels of TRIM8, Proliferating Cell Nuclear Antigen, and Suppressor of Cytokine Signaling 1 (SOCS1) were assessed in CC cell lines. CC cells were transfected with si-TRIM8, followed by cell counting kit-8 (CCK-8) assay, colony formation assay, and Transwell assay. Protein immunoprecipitation assay was employed to examine TRIM8's binding with SOCS1, and the ubiquitination level of SOCS1 was determined after MG132 treatment. Rescue experiments were conducted using si-SOCS1 and si-TRIM8 in combination. Results indicate upregulation of TRIM8 in CC cells. Inhibition of TRIM8 suppressed cell viability, proliferation, invasion, and migration. TRIM8 promoted CC cell proliferation, invasion, and migration of CC cells through ubiquitination-mediated degradation of SOCS1. Inhibition of SOCS1 partially reversed the inhibitory effects of si-TRIM8 on the proliferation, invasion, and migration of CC cells. In conclusion, TRIM8 enhances CC cell proliferation, invasion, and migration via ubiquitination-mediated degradation of SOCS1.
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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.
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Progresión de la Enfermedad , Quinasas Janus , Metástasis Linfática , Neoplasias del Pene , Factor de Transcripción STAT4 , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Masculino , Neoplasias del Pene/patología , Neoplasias del Pene/genética , Neoplasias del Pene/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Metástasis Linfática/patología , Metástasis Linfática/genética , Quinasas Janus/metabolismo , Factor de Transcripción STAT4/metabolismo , Factor de Transcripción STAT4/genética , Regulación Neoplásica de la Expresión Génica , Carcinogénesis/genética , Carcinogénesis/patología , Transducción de Señal , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
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.
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Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Animales , Quinasas Janus/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Haploinsuficiencia , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/genética , Terapia GenéticaRESUMEN
Lead (Pb) is a common pollutant that is not biodegradable and gravely endangers the environment and human health. Annona squamosa fruit has a wide range of medicinal uses owing to its phytochemical constituents. This study evaluated the effect of treatment with A. squamosa fruit extract (ASFE) on testicular toxicity induced in male rats by lead acetate. The metal-chelating capacity and phytochemical composition of ASFE were determined. The LD50 of ASFE was evaluated by probit analysis. Molecular docking simulations were performed using Auto Dock Vina. Forty male Sprague Dawley rats were equally divided into the following groups: Gp1, a negative control group; Gp2, given ASFE (350 mg/kg body weight (b. wt.)) (1/10 of LD50); Gp3, given lead acetate (PbAc) solution (100 mg/kg b. wt.); and Gp4, given PbAc as in Gp3 and ASFE as in Gp2. All treatments were given by oro-gastric intubation daily for 30 days. Body weight changes, spermatological parameters, reproductive hormone levels, oxidative stress parameters, and inflammatory biomarkers were evaluated, and molecular and histopathological investigations were performed. The results showed that ASFE had promising metal-chelating activity and phytochemical composition. The LD50 of ASFE was 3500 mg/kg b. wt. The docking analysis showed that quercetin demonstrated a high binding affinity for JAK-1 and STAT-3 proteins, and this could make it a more promising candidate for targeting the JAK-1/STAT-3 pathway than others. The rats given lead acetate had defective testicular tissues, with altered molecular, biochemical, and histological features, as well as impaired spermatological characteristics. Treatment with ASFE led to a significant mitigation of these dysfunctions and modulated the JAK-1/STAT-3/SOCS-1 axis in the rats.
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Annona , Frutas , Compuestos Organometálicos , Extractos Vegetales , Transducción de Señal , Testículo , Animales , Masculino , Ratas , Annona/química , Frutas/química , Janus Quinasa 1/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patologíaRESUMEN
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 RTâPCR, 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.
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MicroARNs , Proteína 1 Supresora de la Señalización de Citocinas , Toxoplasma , Toxoplasmosis , Adulto , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Enfermedad Crónica , Irak/epidemiología , MicroARNs/genética , MicroARNs/sangre , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Toxoplasma/genética , Toxoplasma/inmunología , Toxoplasmosis/parasitología , Toxoplasmosis/genética , AdolescenteRESUMEN
This study aims to explore the mechanism of pyroptosis of human hepatocyte LX-2 cells induced by NaAsO2 through the miR-150-5p/SOCS1 pathway. LX-2 cells were transfected with different concentrations of NaAsO2, miR-150-5p inhibitor, and SOCS1 agonist. Cell activity, cell pyroptosis, and the expression of related genes and proteins were detected by scanning electron microscopy, CCK-8, qRT-PCR, western blot, and immunofluorescence. Compared with the control group, 10 µmol/L and 20 µmol/L NaAsO2 significantly elevated the protein expression levels of the pyroptosis-related proteins NLRP3, GSDMD, GSDMD-N, caspase1, and cleaved caspase1 as well as the mRNA levels of NLRP3, GSDMD, caspase1, IL-18, and IL-1ß. The typical pyroptosis with swelling and rupture of the plasma membrane was observed through scanning electron microscopy. The expression of miR-150-5p of the NaAsO2 intervention group increased, while the expression of SOCS1 decreased; then the level of NF-κB p65 elevated. With co-treatment of miR-150-5p inhibitor, SOCS1 agonist, and NaAsO2, the cell pyroptosis was attenuated, and the expressions of NLRP3, caspase1, GSDMD, GSDMD-N, IL-18, IL-1ß, p65 of the group of miR-150-5p inhibitor and NaAsO2 group, and of the group of SOCS1 agonist and NaAsO2 reduced compared with the NaAsO2 group. Arsenic exposure promotes miR-150-5p, inhibits the expression of SOCS1, and activates the NF-κB/NLRP3 pathway in LX-2 cell pyroptosis.
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BACKGROUND AND PURPOSE: Atherosclerosis is the primary pathological basis of cardiovascular disease. Ferroptosis is a regulated form of cell death, a process of lipid peroxidation driven by iron, which can initiate and promote atherosclerosis. STAT6 is a signal transducer that shows a potential role in regulating ferroptosis, but, the exact role in ferroptosis during atherogenesis remains unclear. The Traditional Chinese Medicine Maijitong granule (MJT) is used for treating cardiovascular disease and shows a potential inhibitory effect on ferroptosis. However, the antiatherogenic effect and the underlying mechanism remain unclear. In this study, we determined the role of STAT6 in ferroptosis during atherogenesis, investigated the antiatherogenic effect of MJT, and determined whether its antiatherogenic effect was dependent on the inhibition of ferroptosis. METHODS: 8-week-old male LDLR-/- mice were fed a high-fat diet (HFD) at 1st and 10th week, respectively, to assess the preventive and therapeutic effects of MJT on atherosclerosis and ferroptosis. Simultaneously, the anti-ferroptotic effects and mechanism of MJT were determined by evaluating the expression of genes responsible for lipid peroxidation and iron metabolism. Subsequently, we reanalyzed microarray data in the GSE28117 obtained from cells after STAT6 knockdown or overexpression and analyzed the correlation between STAT6 and ferroptosis. Finally, the STAT6-/- mice were fed HFD and injected with AAV-PCSK9 to validate the role of STAT6 in ferroptosis during atherogenesis and revealed the antiatherogenic and anti-ferroptotic effect of MJT. RESULTS: MJT attenuated atherosclerosis by reducing plaque lesion area and enhancing plaque stability in both preventive and therapeutic groups. MJT reduced inflammation via suppressing inflammatory cytokines and inhibited foam cell formation by lowering the LDL level and promoting ABCA1/G1-mediated lipid efflux. MJT ameliorated the ferroptosis by reducing lipid peroxidation and iron dysregulation during atherogenesis. Mechanistically, STAT6 negatively regulated ferroptosis by transcriptionally suppressing SOCS1/p53 and DMT1 pathways. MJT suppressed the DMT1 and SOCS1/p53 via stimulating STAT6 phosphorylation. In addition, STAT6 knockout exacerbated atherosclerosis and ferroptosis, which abolished the antiatherogenic and anti-ferroptotic effects of MJT. CONCLUSION: STAT6 acts as a negative regulator of ferroptosis and atherosclerosis via transcriptionally suppressing DMT1 and SOCS1 expression and MJT attenuates atherosclerosis and ferroptosis by activating the STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways, which indicated that STAT6 acts a novel promising therapeutic target to ameliorate atherosclerosis by inhibiting ferroptosis and MJT can serve as a new therapy for atherosclerosis treatment.
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Aterosclerosis , Proteínas de Transporte de Catión , Medicamentos Herbarios Chinos , Ferroptosis , Factor de Transcripción STAT6 , Proteína 1 Supresora de la Señalización de Citocinas , Animales , Ferroptosis/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Factor de Transcripción STAT6/metabolismo , Masculino , Medicamentos Herbarios Chinos/farmacología , Ratones , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores de LDL/metabolismo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Inflammation affects several aspects of lung cancer progression including cell proliferation, metastasis, apoptosis, angiogenesis, and drug resistance. Baicalin, an active component of Scutellaria baicalensis Georgi, exhibits anticancer activity in various cancers. However, the effects of baicalin on lung cancer and the underlying molecular mechanisms remain largely unknown. This study is to explore the effect and mechanism of baicalin on lung cancer cell A549 and urethane-induced mouse lung cancer. A cell viability assay, colony formation assay, wound healing assay, acridine orange/ethidium bromide (AO/EB) staining assay, Western blot assay, urethane-induced mouse lung cancer model, hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and ELISA assay were performed to investigate the effects of baicalin on lung cancer in vitro and in vivo. Network pharmacology analysis, molecular docking, gene silencing assays, and LPS-induced inflammation model were utilized to explore the molecular mechanisms underlying the effect of baicalin on lung cancer. Baicalin showed significant anti-proliferative, anti-migratory, anti-inflammatory and pro-apoptotic effects in vitro; it also inhibited the progression of urethane-induced mouse lung cancer in vivo. Mechanistically, suppressor of cytokine signaling 1 (SOCS1) was the key determinant for baicalin-induced inhibition of lung cancer. Baicalin increased SOCS1 expression to inactivate the NF-κB/STAT3 pathway to inhibit lung cancer in vitro and in vivo. Taken together, baicalin reduces inflammation to inhibit lung cancer via targeting SOCS1/NF-κB/STAT3 axis, providing a prospective compound and novel target for lung cancer treatment.
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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.
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MicroARNs , ARN Largo no Codificante , Rinitis Alérgica , Animales , Humanos , Ratones , Regulación hacia Abajo , Inmunoglobulina E , Inmunoglobulina G , Ratones Endogámicos BALB C , MicroARNs/genética , Rinitis Alérgica/inducido químicamente , Rinitis Alérgica/genética , ARN Largo no Codificante/genética , Estornudo , Proteína 1 Supresora de la Señalización de Citocinas/genéticaRESUMEN
BACKGROUND: Solid tumors promote tumor malignancy through interaction with the tumor microenvironment, resulting in difficulties in tumor treatment. Therefore, it is necessary to understand the communication between cells in the tumor and the surrounding microenvironment. Our previous study revealed the cancer malignancy mechanism of Bcl-w overexpressed in solid tumors, but no study was conducted on its relationship with immune cells in the tumor microenvironment. In this study, we sought to discover key factors in exosomes secreted from tumors overexpressing Bcl-w and analyze the interaction with the surrounding tumor microenvironment to identify the causes of tumor malignancy. METHODS: To analyze factors affecting the tumor microenvironment, a miRNA array was performed using exosomes derived from cancer cells overexpressing Bcl-w. The discovered miRNA, miR-6794-5p, was overexpressed and the tumorigenicity mechanism was confirmed using qRT-PCR, Western blot, invasion, wound healing, and sphere formation ability analysis. In addition, luciferase activity and Ago2-RNA immunoprecipitation assays were used to study the mechanism between miR-6794-5p and its target gene SOCS1. To confirm the interaction between macrophages and tumor-derived miR-6794-5p, co-culture was performed using conditioned media. Additionally, immunohistochemical (IHC) staining and flow cytometry were performed to analyze macrophages in the tumor tissues of experimental animals. RESULTS: MiR-6794-5p, which is highly expressed in exosomes secreted from Bcl-w-overexpressing cells, was selected, and it was shown that the overexpression of miR-6794-5p increased migratory ability, invasiveness, and stemness maintenance by suppressing the expression of the tumor suppressor SOCS1. Additionally, tumor-derived miR-6794-5p was delivered to THP-1-derived macrophages and induced M2 polarization by activating the JAK1/STAT3 pathway. Moreover, IL-10 secreted from M2 macrophages increased tumorigenicity by creating an immunosuppressive environment. The in vitro results were reconfirmed by confirming an increase in M2 macrophages and a decrease in M1 macrophages and CD8+ T cells when overexpressing miR-6794-5p in an animal model. CONCLUSIONS: In this study, we identified changes in the tumor microenvironment caused by miR-6794-5p. Our study indicates that tumor-derived miR-6794-5p promotes tumor aggressiveness by inducing an immunosuppressive environment through interaction with macrophage.
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Exosomas , MicroARNs , Neoplasias , Animales , Neoplasias/genética , Bioensayo , Transporte Biológico , Linfocitos T CD8-positivos , MicroARNs/genética , Microambiente TumoralRESUMEN
Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary heart disease in comparison to healthy individuals. The downregulation of miR-19a/b has been observed to facilitate the replication of influenza A virus (IAV). miR-19a/b can effectively inhibit IAV replication by targeting and reducing the expression of SOCS1, as observed in cell-based and coronary heart disease mouse models. This mechanism leads to the alleviation of the inhibitory effect of SOCS1 on the interferon (IFN)/JAK/STAT signaling pathway. The results indicate that the IAV employs a unique approach to inhibit the host's type I IFN-mediated antiviral immune responses by decreasing miR-19a/b. These findings provide additional insights into the underlying mechanisms of susceptibility to flu in patients with coronary heart disease. miR-19a/b can be considered as a preventative/therapy strategy for patients with coronary heart disease against influenza virus infection.
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Purpose: This study aimed to detect the role and mechanism of circTMEM59 in pancreatic ductal adenocarcinoma (PDAC). Methods: 66 paired PDAC tissues and normal samples were harvested from patients diagnosed and undergoing pancreatic cancer surgery in our hospital. The expression of circTMEM59 in PDAC tissues and cell lines was detected. Based on bioinformatics information, the circTMEM59 mimics, miR-147b mimics, miR-147b inhibitor and si-suppressor of cytokine signaling 1 (SOCS1) were transfected into PDAC cells. The expression levels of circTMEM59, miR-147b and SOCS1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR). RNA interaction was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell invasion and proliferation were evaluated by Transwell and Cell Counting Kit-8 (CCK-8) assays. The protein expression was detected by Western blot. Results: CircTMEM59 was confirmed to be downregulated in PDAC tumor tissues and cells. Low expression of circTMEM59 was closely correlated with the short survival time and poor clinicopathological characteristics. By up-regulating the expression of circTMEM59 in PDAC cells, cell proliferation, invasion and epithelial-mesenchymal transition (EMT) were inhibited. More importantly, miR-147b could be sponged by circTMEM59, and knockdown of miR-147b inhibited progression of PDAC cells. Further study revealed that SOCS1 was targeted by miR-147b. SOCS1 expression was negatively related to miR-147b expression and positively related to circTMEM59 expression in PDAC tissues. Upregulated miR-147b and downregulated SOCS1 could rescue the effects of circTMEM59 on cell proliferation, EMT and invasion. Conclusion: Our data indicated that circTMEM59 inhibited cell proliferation, invasion and EMT of PDAC by regulating miR-147b/SOCS1 axis.
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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.
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Neoplasias , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Linfocitos T/metabolismoRESUMEN
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.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , ARN Largo no Codificante , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Macrófagos/metabolismo , Línea Celular Tumoral , Microambiente Tumoral , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Factor de Transcripción STAT1/metabolismoRESUMEN
SOCS1 is a tumor suppressor in hepatocellular carcinoma (HCC). Recently, we showed that a loss of SOCS1 in hepatocytes promotes NRF2 activation. Here, we investigated how SOCS1 expression in HCC cells affected oxidative stress response and modulated the cellular proteome. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). The induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed an increased induction of reactive oxygen species but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. A proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways, including mitochondrial ROS generation and ROS detoxification, through peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.