Search

Suppressor of cytokine signaling 2 (SOCS2) plays an essential role in a number of physiological phenomena and functions as a tumor suppressor. Understanding the predictive effects of SOCS2 on non-small cell lung cancer (NSCLC) is urgently needed. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to assess SOCS2 gene expression levels in NSCLC. The clinical significance of SOCS2 was evaluated through Kaplan-Meier curve analysis and the analysis of related clinical factors. Gene Set Enrichment Analysis (GSEA) was used to identify the biological functions of SOCS2. Subsequently proliferation, wound-healing, colony formation and Transwell assays, and carboplatin drug experiments were used for verification. The results revealed that SOCS2 expression was low in the NSCLC tissues of patients in TCGA and GEO database analyses. Downregulated SOCS2 was associated with poor prognosis, as determined by Kaplan-Meier survival analysis (HR 0.61, 95% CI 0.52-0.73; P<0.001). GSEA showed that SOCS2 was involved in intracellular reactions, including epithelial-mesenchymal transition (EMT). Cell experiments indicated that knockdown of SOCS2 caused the malignant progression of NSCLC cell lines. Furthermore, the drug experiment showed that silencing of SOCS2 promoted the resistance of NSCLC cells to carboplatin. In conclusion, low expression of SOCS2 was associated with poor clinical prognosis by effecting EMT and causing drug resistance in NSCLC cell lines. Furthermore, SOCS2 could act as a predictive indicator for NSCLC. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is a crucial pathogenetic mechanism for sepsis. GRB2-associated binder 1 (GAB1) alleviates sepsis-induced multi-organ damage; however, to the best of our knowledge, its function in endothelial dysfunction in sepsis remains unclear. HUVECs were induced by lipopolysaccharide (LPS) to simulate endothelial cell injury under sepsis. Cell transfection was conducted to achieve GAB1 overexpression or suppressor of cytokine signaling 3 (SOCS3) knockdown. The expression levels of GAB1 and SOCS3 were detected by reverse transcription-quantitative PCR and western blotting. Cell viability, apoptosis and migration were assessed using Cell Counting Kit-8, TUNEL and wound healing assays, respectively. The production of cytokines and nitric oxide (NO) was detected using commercial kits. The interaction between GAB1 and SOCS3 was confirmed using a co-immunoprecipitation assay. GAB1 was downregulated in LPS-induced HUVECs. However, GAB1 overexpression significantly mitigated LPS-induced cell viability decrease and apoptosis in HUVECs, accompanied by upregulation of Bcl2 expression, and downregulation of Bax and cleaved caspase-3 expression. GAB1 also inhibited the production of pro-inflammatory cytokines and increased NO level, increased the levels of endothelial NO synthase (eNOS) and phosphorylated (p)-eNOS, and promoted migration in LPS-induced HUVECs. However, SOCS3 knockdown partially weakened the effects of GAB1 overexpression on cell viability, apoptosis, inflammation, p-eNOS, eNOS expression and NO levels in LPS-induced HUVECs. In addition, GAB1 and SOCS3 regulated Janus kinase 2 (JAK2)/STAT3 signaling in LPS-induced HUVECs. In conclusion, GAB1 exerted a protective effect against LPS-induced endothelial cell apoptosis, inflammation and dysfunction by modulating the SOCS3/JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

The weakening of extravillous trophoblast (EVT) invasion results in shallow placenta implantation. In HTR8/SVneo cells, IFN-γ can activate STAT1 and reduce cell invasion, and suppressor of cytokine signaling (SOCS) is an important negative regulatory protein in the Janus kinase (JAK)/STAT activator pathway and has a negative feedback function on JAK/STAT1. The aim of the present study was to elucidate how SOCS1 feedback regulates JAK/STAT1 and affects EVT cell invasion, which in turn affects the development of preeclampsia (PE). MTT and Annexin V/phosphatidylserine (PS) assays were performed to evaluate the viability and apoptosis of HTR8/SVneo cells treated with IFN-γ, respectively. Wound healing and invasion assays were also conducted to measure the migratory and invasive abilities of IFN-γ-treated HTR8/SVneo cells. The mRNA and protein expression levels of genes were detected using reverse transcription-quantitative PCR and western blot analysis. Small interfering RNA knockdown of SOCS1 was used to verify the role of feedback regulation in the IFN-γ-activated JAK/STAT1 signaling pathway. IFN-γ can inhibit HTR8/SVneo migration and invasion, and promote apoptosis by increasing the expression of phosphorylated (p)-JAK, p-STAT1 and caspase3, and reducing the expression of platelet-derived growth factor receptor A and Ezrin. Furthermore, SOCS1 may negatively regulate JAK/STAT1 and affect HTR-8/SVneo invasiveness. Evaluation of clinical samples demonstrated that the expression levels of SOCS1 and IFN-γ were higher in patients with PE compared with the healthy group. Collectively, the present results indicated that IFN-γ reduced the invasion of HTR-8/SVneo cells by activating JAK/STAT1, concurrently leading to an increase in SOCS1, which negatively regulates JAK/STAT1 and eliminates the pro-inflammatory effects of IFN-γ, thus forming a feedback loop. [ABSTRACT FROM AUTHOR]

We aimed to investigate the expression of suppressors cytokine signaling (SOCS)-3, transforming growth factor (TGF)-β and indoleamine 2,3-dioxygense (IDO) and to analyse the relationship of SOCS3 and TGF-β with IDO expression in early pregnancy chorionic villi and decidua in the maternal-fetal interface. Western blot analysis and immunohistochemical method were used to detect the expression of TGF-β, SOCS3 and IDO in chorionic villi and decidua tissues of normal pregnant women. SOCS3, TGF-β and IDO protein was identified in chorionic villi and decidua tissues of normal pregnant women and there was a negative correlation between the expression of IDO and SOCS3, but TGF-β expression was positively correlated with IDO expression. The levels of IDO expression in the decidua from normal pregnancies were significantly higher than those in chorionic villi, while the expression of SOCS3 was no significant difference between decidua and chorionic villi. In normal physiological state of pregnancy, SOCS3 and TGF-β may be involved in the regulation of immune tolerance by positive or negative regulation of IDO expression at maternal fetal interface. [ABSTRACT FROM AUTHOR]

Metformin (MET) is the first-line therapeutic option for patients with type 2 diabetes that has garnered substantial attention over recent years. However, an insufficient number of studies have been performed to assess its effects on insulin resistance and the expression profile of long noncoding RNAs (lncRNAs). The present study divided mice into three groups: Control group, high-fat diet (HFD) group and HFD + MET group. A high-throughput sequencing analysis was conducted to detect lncRNA and mRNA expression levels, and differentially expressed lncRNAs were selected. Subsequently, the differentially expressed lncRNAs were validated both in vivo and in vitro (mouse liver AML12 cells treated with Palmitic acid) models of insulin resistance. After validating randomly selected lncRNAs via reverse transcription-quantitative PCR a novel lncRNA, NONMMUT031874.2, was identified, which was upregulated in the HFD group and reversed with MET treatment. To investigate the downstream mechanism of NONMMUT031874.2, lncRNA-microRNA (miR/miRNA)-mRNA co-expression network was constructed and NONCODE, miRBase and TargetScan databases were used, which indicated that NONMMUT031874.2 may regulate suppressor of cytokine signaling 3 by miR-7054-5p. For the in vitro part of the present study, AML12 cells were transfected with small interfering RNA to knock down NONMMUT031874.2 expression before being treated with palmitic acid (PA) and MET. The results showed that the expression of NONMMUT031874.2 was significantly increased whereas miR-7054-5p expression was significantly decreased by PA treatment. By contrast, after knocking down NONMMUT031874.2 expression or treatment with MET, the aforementioned in vitro observations were reversed. In addition, it was also found that NONMMUT031874.2 knockdown and treatment with MET exerted similar effects in alleviating insulin resistance and whilst decreasing glucose concentration in AML12 cells. These results suggest that MET treatment can ameliorate insulin resistance by downregulating NONMMUT031874.2 expression. [ABSTRACT FROM AUTHOR]

microRNAs (miRs) have been indicated to serve oncogenic or tumor suppressor roles. However, the role of miR-483-5p in breast cancer and its associated molecular mechanisms remain unclear. In the present study, compared with adjacent normal tissues and MCF-10a cells, the expression level of miR-483-5p was upregulated in triple-negative breast cancer (TNBC) tissues and TNBC cell lines. Bioinformatic analysis and luciferase reporter assay confirmed the presence of miR-483-5p binding sites in the 3'-untranslated region of suppressor of cytokine signaling 3 (SOCS3). In addition, the expression level of SOCS3 protein in TNBC tissues was markedly lower compared with in adjacent tissues, and miR-483-5p expression was negatively correlated with SOCS3 expression in TNBC tissues. Cell proliferation and flow cytometry assays indicated that knockdown of miR-483-5p inhibited the proliferation and promoted apoptosis in the TNBC cell line BT-549. This effect was markedly attenuated by SOCS3 small interfering (si)RNA transfection. Additionally, wound healing and Transwell assays demonstrated that SOCS3 siRNA reversed the inhibitory effects of miR-483-5p inhibitor on the migration and invasion of BT-549 cells. Moreover, the decrease in miR-483-5p expression significantly reduced the secretion of TNF-α, IL-6, IL-1β and monocyte chemoattractant protein-1 in BT-549 cells, while SOCS3 siRNA could partially reverse this effect. Additionally, SOCS3 overexpression reversed the effects of miR-483-5p mimic on the proliferation, migration, invasion and inflammation of BT-549 cells. Taken together, these data demonstrated that the inhibition of miR-483-5p could inhibit the proliferation, migration, invasion and inflammatory response, while promoting the apoptosis of TNBC cells by negatively regulating SOCS3. miR-483-5p may be a potential target for TNBC therapy. [ABSTRACT FROM AUTHOR]

The expression levels of microRNA (miR)-221-3p and miR-222-3p in thyroid cancer have been found to be upregulated compared with those in normal tissues. The present study aimed to determine the effects and potential underlying mechanisms of miR-221-3p and miR-222-3p on the regulation of radioactive iodine (131I) uptake and radiosensitivity of thyroid cancer cells. The potential regulatory target genes of miR-221-3p and miR-222-3p were predicted by bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction was used to verify miR-221-3p, miR-222-3p and target gene expression levels in thyroid cancer tissues and cell lines. Overexpression of miR-221-3p or miR-222-3p in cell models was performed using lentivirus infection. Knockdown of miR-221-3p and miR-222-3p in cells was achieved using oligonucleotide inhibitor transfection. Western blotting was used to analyze the expression levels of target proteins. In addition, the effects of miR-221-3p and miR-222-3p on the radiosensitivity of thyroid cancer cells were verified using a colony formation assay. The results of the present study revealed that the expression levels of miR-221-3p and miR-222-3p were significantly upregulated, while the expression levels of suppressor of cytokine signaling 3 (SOCS3) were downregulated in thyroid cancer tissues. Furthermore, miR-221-3p and miR-222-3p overexpression downregulated the expression levels of SOCS3, E-cadherin and solute carrier family 5 member 5 (NIS), and upregulated the expression levels of phosphorylated STAT3 and vimentin. Following the overexpression of miR-221-3p or miR-222-3p in the FTC133 and TPC1 cell lines, their radiosensitivity was suppressed. In conclusion, the findings of the present study suggested that miR-221-3p and miR-222-3p may downregulate the expression levels of NIS and promote radioresistance. The potential mechanism was hypothesized to be associated with the miR-221-3p and miR-222-3p targeting of the SOCS3 gene, which may subsequently activate the STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]