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Aberrant expression of miRNAs is significantly correlated with the occurrence of immune thrombocytopenic purpura (ITP). The immune imbalance of M1/M2 macrophage contributes to the development of ITP. However, the role of miR-148b-3p in macrophage phenotype imbalance remains unknown in ITP. In this study, we aimed to explore whether miR-148b-3p inhibits M2 macrophage polarization in ITP and to investigate the underlying mechanism. Peripheral blood from 22 ITP patients were collected, and real-time PCR confirmed that miR-148b-3p was upregulated and Western blot analyses detected the expression of SOCS3 was down-regulated. Subsequent dualluciferase reporter gene assay indicated that miR-148b-3p could bind to SOCS3. Furthermore, we found significant correlation between miR-148b-3p expression and platelet count. Applying gain and lose the function experiments of miR-148b-3p and SOCS3, we demonstrated that suppression of miR-148b-3p or up-regulation of SOCS3 promoted macrophage M2 polarization by inhibiting JAK2/STAT3 pathway. Together, our findings demonstrate that that miR148b-3p targeting SOCS3 inhibits M2 macrophage polarization via JAK2/STAT3 signaling in ITP. [ABSTRACT FROM AUTHOR]

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Abstract Schistosomiasis is endemic in many parts of rural Africa, with previous reports showing interleukin-13 polymorphisms as drivers of infectivity and disease severity in West Africa while IL-13/IL-4 polymorphisms contributes to patterns of reinfection in East Africa. We have shown that there is a genetic delineation in susceptibility to and severity of infectious diseases in Africa, in addition to sub-continental differences in disease pattern. Therefore, which immunoregulatory biomarkers are essential in driving S. haematobium infection or regulate disease burden among Nigerian school children? One hundred and thirty one age and sex-matched schistosome-infected children and 275 uninfected controls, of same ethnicity, recruited from southwestern Nigeria, were screened for variability of cytokine genes, IL-10 (rs1800872), IL-13 (rs7719175), IL-4 (rs2243250) and STAT6 (rs3024974), utilizing a polymerase chain reaction-restriction fragment length polymorphism assay. We found no difference in genotypic or allelic frequencies of IL-10 and IL-13 promoter polymorphisms alone or in association with disease. Contrariwise, we report significant differences in the frequencies of IL-4 and STAT6 variants between groups. For IL-4, the rs2243250 T/T variant was significantly different for genotypes (71.6% versus 51.2%; p <.0004) and alleles (82.6% versus 71.1%; p <.001) between disease and control groups respectively. For STAT6 (rs3024974), the frequencies of genotypes C/C and C/T are 75.4% and 24.6%, both showing an association with disease; none of the infected subjects had the T/T variant. Despite minor differences in disease covariates, we found no association between IL-4 and STAT6 variants with age, gender or anemia. However, mean egg count (indicative of disease burden), was regulated based on IL-4 variants, with highest burden in infected subjects with rs2243250 T/T variant (mean egg count: 207.5 eggs/10 ml of urine) versus rs2243250 C/T heterozygotes (mean egg count: 84.3 eggs/10 ml of urine) versus rs2243250 C/C (mean egg count: 127.9 eggs/10 ml of urine). Comparing rs2243250 C/T versus rs2243250 T/T (p <.008) or rs2243250 C/C + C/T versus rs2243250 T/T (p <.016) reveals an association with disease burden. We conclude that the IL-4 promoter gene is a susceptibility factor for schistosomiasis, and essential to regulate disease burden, with worse disease among carriers of the rs2243250 T/T variant. The absence of the STAT6, rs3024974T/T variant among infected subjects reveal the necessity of the STAT6 promoter gene in driving susceptibility to schistosomiasis in Nigeria. Highlights • Schistosoma haematobium infected school children in Nigeria were recruited into this study • We elucidated the role of IL-4, IL-10, IL-13 and STAT6 promoter genes in schistosome-infected versus uninfected controls • We report that IL-4 (rs2243250) and STAT6 (rs3024974) genes are drivers of disease susceptibility among school children • In addition, IL-4 (rs2243250) promoter variants are essential to regulate disease burden • Highest mean egg count and significantly worse disease burden among carriers of the rs2243250TT variant [ABSTRACT FROM AUTHOR]

Interferon-α (IFNα) has one of the longest histories of use amongst cytokines in clinical oncology and has been applied for the treatment of many types of cancers. Due to its immune-activating properties, IFNα is also an attractive candidate for combinatory anti-cancer therapies. Despite its extensive use in animal tumor models as well as in several clinical trials, the differentmechanisms underlying patient responses and affecting desirable clinical benefits are still under investigation. Here we show that in addition to its immune-activating properties, IFNα induces the expression of a key negative regulator, immunosuppressive PD-L1molecule, in themajority of the specific immune cell populations, particularly in the dendritic cells (DC). DC can modulate immune responses by a variety of mechanisms, including expression of T-cell regulatory molecules and cytokines. Our results showed that treatment of DC with IFNα-2b led to pronounced up-regulation of surface expression of PD-L1 molecules, increased IL-6 and decreased IL-12 production. Moreover, we present evidence that IFNα-treated DC exhibited a reduced capacity to stimulate interferon-γ production in T cells compared to control DC. This T-cell response after treatment of DC with IFNα was recovered by a pre-treatment with an anti-PD-L1 blocking antibody. Further analyses revealed that IFNα regulated PD-L1 expression through the STAT3 and p38 signaling pathways, since blocking of STAT3 and p38 activation with specific inhibitors prevented PD-L1 up-regulation. Our findings underline the important roles of p38 and STAT3 in the regulation of PD-L1 expression and prove that IFNα induces STAT3/p38-mediated expression of PD-L1 and thereby a reduced stimulatory ability of DC. The augmentation of PD-L1 expression in immune cells through IFNα treatment should be considered by use of IFNα in an anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Huntington’s disease is a late onset neurological disorder caused by a trinucleotide CAG repeat expansion mutation in the HTT gene encoding for the protein huntingtin. Despite considerable ongoing research, the wild-type function of huntingtin is not yet fully understood. Objective: To improve knowledge of HTT gene regulation at the transcriptional level and inform future studies aimed at uncovering the HTT gene’s normal function. Methods: The HTT gene region was functionally characterized through an in silico analysis using publicly available data sets. ChIP-seq data sets and the online STRING database were used to identify putative transcription factor binding sites (TFBSs) and protein-protein interactions within the HTT promoter region. siRNA-mediated knockdown and ChIP-qPCR of STAT1, a TF identified from the in silico analysis, were used to validate the bioinformatics screen. Results: 16 regions containing potential regulatory genomic markers were identified. TFBSs for 59 transcription factors (TFs) were detected in one or more of the 16 candidate regions. Using these TFs, 15 clusters of protein-protein interactions were identified using STRING. siRNA-mediated knockdown of STAT1 resulted in an increase in HTT expression, and ChIP-qPCR detected enrichment of STAT1 binding at one of the predicted regions. These assays confirmed the utility of the bioinformatic analysis. Conclusions: Putative regulatory regions outside of the immediate HTT promoter region have been identified with specific protein-protein interactions. Future work will focus on in vitro and in vivo studies to examine the effect of modulating identified TFBSs and altering the levels of specific TFs of interest in regulating HTT gene expression. [ABSTRACT FROM AUTHOR]

'Njavara' ( Oryza sativa L.) is a unique rice variety grown in Kerala that is reported to have significantly higher antioxidant, anti-inflammatory, chemical indices, and bioactive components compared with staple rice varieties. However, the role of NBE in reversing the atherosclerosis development remains unclear. The present study aimed to elucidate the role of NBE in promoting atherosclerotic regression. Male New Zealand white breed rabbits were divided into three groups. Group I was the control, group II was the regression control, and group III was NBE treated (100 mg/kg body mass). Serum and tissue lipids, CRP, antioxidant enzyme activities, mRNA, and protein expression of genes of RTC and mRNA expression of cytokines were studied. The current study showed that hypercholesterolemic rabbits treated with NBE decreased the serum and tissue lipids concentrations, ApoB expression, and CRP levels and enhanced the activities of antioxidant enzymes and PON1expression, JAK2, STAT3, ABCA1, and ApoA. Our results indicate that NBE attenuates proinflammatory cytokine production (IL-1β), enhanced expression and interactions of ABCA1/ApoA1 leading to JAK2/STAT3 activation in macrophages switching to an anti-inflammatory milieu in the system, and enhanced expression of IL-10 and decreased expression of ApoB, indicating that treatment with NBE facilitates plaque regression. [ABSTRACT FROM AUTHOR]

Cytokines critically control immune responses, but how regulatory programs are altered to allow T cells to differentially respond to distinct cytokine stimuli remains poorly understood. Here, we have globally analyzed enhancer elements bound by IL-2-activated STAT5 and IL-21-activated STAT3 in T cells and identified Il2ra as the top-ranked gene regulated by an IL-2-activated STAT5-bound superenhancer and one of the top genes regulated by STAT3-bound superenhancers. Moreover, we found that STAT5 binding was rapidly superenriched at genes highly induced by IL-2 and that IL-2-activated STAT5 binding induces new and augmented chromatin interactions within superenhancer-containing genes. Based on chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing data, we used CRISPR-Cas9 gene editing to target three of the STAT5 binding sites within the Il2ra superenhancer in mice. Each mutation decreased STAT5 binding and altered IL-2-induced Il2ra gene expression, revealing that individual elements within the superenhancer were not functionally redundant and that all were required for normal gene expression. Thus, we demonstrate cooperative utilization of superenhancer elements to optimize gene expression and show that STAT5 mediates IL-2-induced chromatin looping at superenhancers to preferentially regulate highly inducible genes, thereby providing new insights into the mechanisms underlying cytokine-dependent superenhancer function. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 2 (STAT2) is a key element that transduces signals from the cell membrane to the nucleus via the type I interferon-signaling pathway. Although the structural and functional aspects of STAT proteins are well studied in mammals, information on teleostean STATs is very limited. In this study, a STAT paralog, which is highly homologous to the STAT2 members, was identified from a commercially important fish species called rock bream and designated as RbSTAT2. The RbSTAT2 gene was characterized at complementary DNA (cDNA) and genomic sequence levels, and was found to possess structural features common with its mammalian counterparts. The complete cDNA sequence was distributed into 24 exons in the genomic sequence. The promoter proximal region was analyzed and found to contain potential transcription factor binding sites to regulate the transcription of RbSTAT2 . Phylogenetic studies and comparative genomic structure organization revealed the distinguishable evolution for fish and other vertebrate STAT2 orthologs. Transcriptional quantification was performed by SYBR Green quantitative real-time PCR (qPCR) and the ubiquitous expression of RbSTAT2 transcripts was observed in all tissues analyzed from healthy fish, with a remarkably high expression in blood cells. Significantly ( P < 0.05) altered transcription of RbSTAT2 was detected after immune challenge experiments with viral (rock bream irido virus; RBIV), bacterial ( Edwardsiella tarda and Streptococcus iniae ), and immune stimulants (poly I:C and LPS). Antiviral potential was further confirmed by WST-1 assay, by measuring the viability of rock bream heart cells treated with RBIV. In addition, results of an in vitro challenge experiment signified the influence of rock bream interleukin-10 (RbIL-10) on transcription of RbSTAT2 . Subcellular localization studies by transfection of pEGFP-N1/RbSTAT2 into rock bream heart cells revealed that the RbSTAT2 was usually located in the cytoplasm and translocated near to the nucleus upon poly I:C administration. Altogether, these findings suggest that RbSTAT2 is involved in various biologically crucial mechanisms, and provides immune protection to the rock bream. [ABSTRACT FROM AUTHOR]

Neutrophilic airway inflammation in chronic lung infections caused by Pseudomonas aeruginosa (PA) is associated with T helper (Th)17 responses. Suppressor of cytokine signaling 3 (SOCS3) is the major negative modulator of Th17 function through the suppression of signal transducer and activator of transcription (STAT)3 activation. The aim of the present study was to investigate the expression of SOCS3 in lung CD4+ T cells in a mouse model of chronic PA lung infection and the effect of exogenous SOCS3 on Th17-mediated neutrophil recruitment in vitro. A mouse model of chronic PA lung infection was established and the activation of STAT3 and Th17 response in lung tissues and lung CD4+ T cells was assessed. The protein and mRNA expression of SOCS3 in lung CD4+ T cells was analyzed by western blotting and reverse transcription-quantitative polymerase chain reaction. The authors constructed a recombinant lentivirus carrying the SOCS3 gene and transferred it into lung CD4+ T cells isolated from a mouse model. These transfected cells were stimulated with interleukin (IL)-23 in vitro a nd t he p rotein l evel of p-STAT3 and retinoid-related orphan receptor (ROR)γt was determined by western blotting. The expression of IL-17A+ cells was analyzed by flow cytometry and the level of IL-17A in cell culture supernatant was measured by ELISA. The mouse lung epithelial cell line, MLE-12, was cocultured with lung CD4+ T cells that overexpressed the SOCS3 gene and the culture supernatant was harvested and used for a chemotaxis assay. Compared with control mice, mice with chronic PA lung infection had significantly higher level of p-STAT3 and Th17 response in both lung tissues and lung CD4+ T cells. The protein and mRNA level of SOCS3 in lung CD4+ T cells increased as the chronic PA lung infection developed. Exogenous SOCS3 gene transfer in PA-infected lung CD4+ T cells decreased p-STAT3 and RORγt expression and suppressed the level of IL-17A+ cells in vitro. MLE-12 cells cocultured with SOCS3-overexpressing lung CD4+ T cells expressed a significantly lower level of neutrophil chemoattractants chemokine (C-X-C motif) ligand (CXCL) 1 and CXCL5, and recruited significantly smaller numbers of migrating neutrophils than those cocultured with control cells. SOCS3 was upregulated in lung CD4+ T cells following the activation of STAT3/Th17 axis in a mouse model of chronic PA lung infection. Exogenous SOCS3 transfer in PA-infected lung CD4+ T cells suppresses Th17-mediated neutrophil recruitment in vitro. [ABSTRACT FROM AUTHOR]

In this study, it was aimed to investigate polymorphisms in seven genes (GH, PRL, STAT5A, OPN, PIT-1, LEP and FGF2) related to reproductive traits in dairy heifers. Frequency distributions of the genotypes between fertile and repeat breeder heifers groups were investigated. Allele effects on fertility were also analyzed. Blood samples were taken from a total of 160 Holstein-Friesian heifers and they were divided into two groups according to their artificial insemination numbers (AI). The heifers becoming pregnant after the first AI were used as the fertile heifers (FH, n=80) and the heifers with 3 or more equal AIs were accepted as the repeat breeder heifers (RBH, n=80). All the animals were genotyped by the PCR-RFLP method for seven genes and the association works were performed for 145 animals (RBH, n=79; FH n=66). For all loci investigated, two alleles and three genotypes were found for overall population with the exception that PRL locus had two alleles and two genotypes. The chi-square test (Χ²) revealed that the whole population and the two groups separately were at Hardy-Weinberg equilibrium. The genotype distributions of PIT-1 and STAT5A conspicuously differed between the FH and the RBH groups; however, these differences were not found significant. Association of GH-AB genotype was found significant on AI number for the first pregnancy. Mixed effect logistic regression model was used to investigate the allele effects on fertility. No linkage disequilibrium was detected between the investigated loci. [ABSTRACT FROM AUTHOR]

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

IFNs are effective in inhibiting angiogenesis in preclinical models and in treating several angioproliferative disorders. However, the detailed mechanisms of IFNα-mediated anti-angiogenesis are not completely understood. Stat1/2/3 and PML are IFNα downstream effectors and are pivotal regulators of angiogenesis. Here, we investigated PML's role in the regulation of Stat1/2/3 activity. In Pml knock-out (KO) mice, ablation of Pml largely reduces IFNα angiostatic ability in Matrigel plug assays. This suggested an essential role for PML in IFNα's antiangiogenic function. We also demonstrated that PML shared a large cohort of regulatory genes with Stat1 and Stat3, indicating an important role of PML in regulating Stat1 and Stat3 activity. Using molecular tools and primary endothelial cells, we demonstrated that PML positively regulates Stat1 and Stat2 isgylation, a ubiquitination-like protein modification. Accordingly, manipulation of the isgylation system by knocking down USP18 altered IFNα-PML axis-mediated inhibition of endothelial cell migration and network formation. Furthermore, PML promotes turnover of nuclear Stat3, and knockdown of PML mitigates the effect of LLL12, a selective Stat3 inhibitor, on IFNα-mediated anti-angiogenic activity. Taken together, we elucidated an unappreciated mechanism in which PML, an IFNα-inducible effector, possess potent angiostatic activity, doing so in part by forming a positive feedforward loop with Stat1/2 and a negative feedback loop with Stat3. The interplay between PML, Stat1/Stat2, and Stat3 contributes to IFNα-mediated inhibition of angiogenesis, and disruption of this network results in aberrant IFNα signaling and altered angiostatic activity. [ABSTRACT FROM AUTHOR]

Targeting signal transducer and activator of transcription 3 (STAT3) is a potential anticancer strategy. However, STAT3 inhibitors with good selectivity and bioavailability are rare. The aim of this study was to discover selective direct STAT3 inhibitors with good druglikeness. By the advanced multiple ligand simultaneous docking (AMLSD) method, compound 9 was designed as an orally bioavailable STAT3 inhibitor that presented superior druggability and selectivity compared with other representative STAT3 inhibitors. 9 directly and selectively inhibited the pY705 site of STAT3 with an affinity (Ki) of 440 nM. The IC50 of 9 for MDA-MB-231 breast cancer cells was 184-fold lower than its IC50 for MCF-10A normal breast epithelial cells. 9 in vivo induced significant antitumor responses (better than gefitinib), and its therapeutic index should be over 100, indicating good safety of 9. [ABSTRACT FROM AUTHOR]

Two-component systems are a dominant form of bacterial signal transduction. The prototypical two-component system consists of a sensor that responds to a specific input(s) by modifying the output of a cognate regulator. Because the output of a two-component system is the amount of phosphorylated regulator, feedback mechanisms may alter the amount of regulator, and/or modify the ability of a sensor or other proteins to alter the phosphorylation state of the regulator. Two-component systems may display intrinsic feedback whereby the amount of phosphorylated regulator changes under constant inducing conditions and without the participation of additional proteins. Feedback control allows a two-component system to achieve particular steady-state levels, to reach a given steady state with distinct dynamics, to express coregulated genes in a given order, and to activate a regulator to different extents, depending on the signal acting on the sensor. [ABSTRACT FROM AUTHOR]

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm harboring NAB2-STAT6 fusion, which drives STAT6 nuclear relocation. For extrathoracic SFTs, the clinical relevance of this molecular hallmark remains obscure. We assessed STAT6 immunoexpression for 61 extrathoracic SFTs exclusive of the meninges and head and neck, and 25 had analyzable RNAs to distinguish fusion variants by RT-PCR. The immunohistochemical and molecular findings were correlated with clincopathological features and disease-free survival (DFS). Twenty-eight males and 33 females had SFTs in the body cavities ( n = 31), extremities ( n = 17), and trunk ( n = 13), categorized into 53 non-malignant and 8 malignant tumors. The vast majority (n = 57, 93%) exhibited distinctive STAT6 nuclear expression, including malignant ones. The common fusion variants were NAB2ex6-STAT6ex16/ 17 in 13 SFTs and NAB2ex4-STAT6ex2 in 8, while miscellaneous variants were detected only in 4 SFTs in the limbs and trunk but not in any body cavity-based cases ( P = 0.026). The worse DFS was univariately associated with malignant histology ( P = 0.04) but unrelated to tumor size, location, or fusion variant. Conclusively, extrathoracic SFTs mostly harbor NAB2ex6-STAT6ex16/ 17, followed by NAB2ex4-STAT6ex2. Miscellaneous variants are significantly rare in SFTs within the body cavities. The clinical aggressiveness of extrathoraic SFTs is associated with malignant histology but unrelated to the NAB2-STAT6 fusion variants. [ABSTRACT FROM AUTHOR]

The constitutive activation of signal transducer and activator of transcription 5 (STAT5) occurs during the transformation of fusion genes in leukemia. We aimed to investigate whether or not the genetic polymorphisms in theSTAT5gene are associated with the treatment outcomes of Ara-C-based chemotherapy regimens in patients with acute myeloid leukemia (AML). A total of 152 patients with AML were included in our study. Peripheral blood samples were analyzed through matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Results showed that the frequency of rs2293157 T/T was higher in the complete remission and partial remission groups after Ara-C-based chemotherapy even though the genotype had a high frequency in the intermediate risk groups (p < 0.05). We concluded that rs2293157 is an important marker for the therapeutic efficiency of Ara-C-based chemotherapy in patients with AML, especially in the Chinese population. [ABSTRACT FROM AUTHOR]

Genes in the signal transducer and activator of transcription (STAT) family are vital for activities including gene expression and immune response. To investigate the functions of the silkworm Bombyx mori STAT ( Bm-STAT ) gene in antiviral immunity, two Bm-STAT gene isoforms, Bm-STAT -L for long form and Bm-STAT- S for short form, were cloned. Sequencing showed that the open reading frames were 2313 bp encoding 770 amino acid residues for Bm-STAT -L and 2202 bp encoding 734 amino acid residues for Bm-STAT- S. The C-terminal 42 amino acid residues of Bm-STAT-L were different from the last 7 amino acid residues of Bm-STAT-S. Immunofluorescence showed that Bm-STAT was primarily distributed in the nucleus. Transcription levels of Bm-STAT in different tissues were determined by quantitative PCR, and the results revealed Bm-STAT was mainly expressed in testes. Western blots showed two bands with molecular weights of 70 kDa and 130 kDa in testes, but no bands were detected in ovaries by using anti-Bm-STAT antibody as the primary antibody. Expression of Bm-STAT in hemolymph at 48 h post infection with B. mori macula-like virus (BmMLV) was slightly enhanced compared with controls, suggesting a weak response induced by infection with BmMLV. Hemocyte immunofluorescence showed that Bm-STAT expression was elevated in B. mori nucleopolyhedrovirus (BmNPV)-infected cells. Moreover, resistance of BmN cells to BmNPV was reduced by downregulation of Bm-STAT expression and increased by upregulation. Resistance of BmN cells to BmCPV was not significantly improved by upregulating Bm-STAT expression. Therefore, we concluded that Bm-STAT is a newly identified insect gene of the STAT family. The JAK-STAT pathway has a more specialized role in antiviral defense in silkworms, but JAK-STAT pathway is not triggered in response to all viruses. [ABSTRACT FROM AUTHOR]

TLR4 triggers LPS signaling through the adaptors Toll/IL-1R domain-containing adaptor molecule (TICAM)-2 (also called TRAM) and TICAM-1 (also called TRIF), together with Toll/IL-1R domain-containing adaptor protein (TIRAP) and MyD88. The MyD88 pathway mediates early phase responses to LPS on the plasma membrane, whereas the TICAM pathway mediates late-phase responses, which induce the production of type I IFN and activation of inflammasomes. TICAM-2 bridges TLR4 and TICAM-1 for LPS signaling in the endosome. Recently, we identified an acidic motif, E87/D88/D89 in TICAM-2, that provides the interaction surfaces between TICAM-2 and TICAM-1. In the present study, we found additional D91/E92 in TICAM-2, conserved across species, that is crucial for TICAM-1 activation. The D91A/E92A mutant protein was distributed largely to the cytosol, despite myristoylation, suggesting its importance for assistance of membrane localization of TICAM-2. An ectopically expressed D91A/E92A mutant per se failed to activate TICAM-1, unlike its wild-type counterpart that forms self-aggregation, but it still retained the ability to pass LPS-mediated IFN regulatory factor (IRF)3 activation. In a TICAM-2 knockout human cell line expressing TLR4/MD-2 with or without CD14, overexpression of the D91A/E92A mutant did not activate IRF3, but upon LPS stimulation, it induced sufficient TLR4-mediated IRF3 activation with high coefficient colocalization. Hence, the D91/E92 motif guides TICAM-2 membrane localization and self-activation for signaling. Our results suggest the presence of two distinct steps underlying endosomal LPS signaling on TICAM-2 for TICAM-1 activation: TICAM-2 assembling in TLR4 and/or TICAM-2 self-activation. D91A/E92A of TICAM-2 selectively associates the TLR4-dependent TICAM-2 assembling, but not cytosolic TICAM-2 self-aggregation, to activate TICAM-1. [ABSTRACT FROM AUTHOR]

Effective treatment of cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31 + E-selectin + population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E-selectin provides an effective approach for tissue-specific drug delivery to the bone marrow. Tumor growth in the bone can be effectively inhibited by blockage of the STAT3 signaling. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription (STATs), their inhibitors and cyclooxygenase-2 (COX-2) participate in transformations of many various types of cancers. The aim of the present study was to evaluate the relationship between STAT5A/B, COX-2, and PIAS3 mRNA expression and tumor staging, metastasis status, and histopathological subtype in 71 patients with confirmed non-small cell lung cancer (NSCLC) diagnosis. Total RNA was isolated from NSCLC tissue samples and the expression of the studied genes was assessed using TaqMan probes in real-time PCR assay. The expression levels of STAT5A, STAT5B, and COX-2 genes were increased in 69%, 79%, and 71% NSCLC samples respectively, while PIAS3 expression was decreased in the majority (69%) of the studied tissues. Statistically significant differences were observed between STAT5 isoforms (P = 0.0008), with higher expression of STAT5B. We found statistically significant positive correlation between STAT5B and COX-2 (rho = 0.045), and significant negative correlation between STAT5B and PIAS3 (rho = −0.049). The negative correlation between STAT5B and PIAS3 (rho = −0.43) was also observed in T2a+T2b tumor group. Additionally, STAT5B and COX-2 expression levels were significantly different between T1a+T1b and T2a+T2b tumors (P = 0.002 and P = 0.041, respectively), with higher expression of both genes in T2 tumor stage. PIAS3 expression was significantly lower in NSCC subtype as compared with SCC subtype (P = 0.017). Also, STAT5A and STAT5B immunoexpression was assessed, and the results indicated significantly higher protein levels in NSCLC patients as compared with controls (P = 0.048 and P = 0.034, respectively). High STAT5B immunoexpression was positively correlated with STAT5B gene expression in tumors (rho = 0.755). STAT5B protein level was also significantly higher in T2a+T2b tumors, reflecting high STAT5B gene expression in this group. There was no statistically significant association between mRNA and protein expression levels of the studied genes and patients' characteristics: age, gender, smoking. The obtained results highlight the importance of the genes STAT5B and COX-2 in lung cancer progression. [ABSTRACT FROM AUTHOR]

Abstract: Based on the fact that the transcription of STAT-1 plus its Serine 727 and Tyrosine 701 phosphorylation is not the pre-requisite for the cell death signal transduction in the IFN-γ signaling pathway induced by co-immobilized IFN-γ/TNF-α, we investigate both in vitro and in vivo the key transcription regulators to promote the signal transduction of HeLa cells. It is found that IFN-γ R2 is the important death signal receptor in the HeLa cell death by RNA interference. Checking the expression of the whole transcription (STAT) protein family reveals that STAT-6 is highly expressed in comparison with the other STAT proteins. The gene silence of IFN-γ R2 leads to the down-regulation of STAT-6 and phosphorylation-STAT-6 (p-STAT-6) expressions. The successful gene silence of STAT-6 results in the reduction of HeLa cell programmed death and the expression of several important key factors related to programmed cell death (p53, Bcl-2, and Bax). More importantly, our in vivo experiments by injecting nanoparticle drug carriers with the co-immobilized IFN-γ/TNF-α into nude mice model confirm the high expression of STAT-6 and p-STAT-6. It is thus concluded that, in response to IFN-γ, the co-immobilized IFN-γ/TNF-α unusually promotes the activation of STAT-6 rather than STAT-1, resulting in the enhanced cell programmed death in HeLa. The present work reveals the gene-level molecular mechanism of IFN-γ/TNF-α co-immobilized on biomaterials as a potentially effective therapy against cancer cells. [Copyright &y& Elsevier]

Pituitary tumor-transforming gene (PTTG), the index mammalian securin, is abundantly expressed in several tumors and regulates tumor growth and progression. Molecular mechanisms elucidating PTTG regulation and actions remain elusive. Here, we provide evidence that PTTG acts as a signal transducer and activator of transcription factor 3 (STAT3) target gene. Total STAT3 and Tyr705 phosphorylated STAT3 were concordantly expressed with PTTG in human colorectal tumors (n=97 and n=95, respectively, P<0.001). STAT3 specifically bound the human PTTG promoter and induced PTTG transcriptional activity (twofold) as assessed by chromatin immunoprecipitation and luciferase reporter assays. STAT3 transfection increased PTTG mRNA and protein abundance twofold in HCT116 human colon cancer cells, and induction was further enhanced (threefold) by constitutively active STAT3 (STAT3-C), whereas strongly abrogated by dominant-negative STAT3 (STAT3-DN). Attenuating PTTG expression by siRNA in STAT3 HCT116 stable transfectants suppressed cell growth and colony formation in vitro, and PTTG cell knockout also constrained activated STAT3-induced explanted murine tumor growth in vivo. STAT3 increased HCT116 cell migration and invasion up to fivefold, whereas cell mobility was abolished by STAT3-DN (>85%). Impairing PTTG expression by siRNA also strongly suppressed STAT3-faciliated cell migration and invasion by up to 90%. Knocking out PTTG in STAT3-C HCT116 stable transfectants strongly decreased tumor metastases in nude mice, indicating the requirement of PTTG for STAT3-promoted metastasis. These results elucidate a mechanism for tumor cell PTTG regulation, whereby STAT3 induces PTTG expression to facilitate tumor growth and metastasis, and further support the rationale for targeting PTTG to abrogate colorectal cancer growth. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are common systemic autoimmune diseases with genetic and environmental predisposing factors. Signal transducer and activator of transcription 4 (STAT4) transmits signals induced by interleukin-12, interleukin-23 and interferon-γ, which are key cytokines and play important roles in the development of autoimmune diseases. Previous studies confirmed the STAT4 rs7574865 G/T locus to be associated with RA. Thus we conducted a replication study to investigate STAT4 rs7574865 G/T polymorphism and RA/AS susceptibility in a Chinese population. Methods: We studied STAT4 rs7574865 G/T gene polymorphism in 520 patients with RA, 100 AS patients and 520 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results: When the STAT4 rs7574865 GG homozygote genotype was used as the reference group, the GT or GT/TT genotypes were associated with the risk for RA. After stratification analyses, a significantly increased risk for RA associated with the STAT4 rs7574865 GT genotype was evident among the rheumatoid factor (RF)-positive patients, patients with higher erythrocyte sedimentation rate (ESR) level and patients with higher RA disease activity score (DAS28) compared with the STAT4 rs7574865 GG genotype. A significantly increased risk for RA associated with the STAT4 rs7574865 TT genotype was evident among older patients and RF-negative patients compared with the STAT4 rs7574865 GG genotype. STAT4 rs7574865 G/T was not associated with susceptibility to AS. Conclusion: This replication study confirmed that STAT4 rs7574865 G/T polymorphism was associated with the risk of RA. Condensed abstract: STAT4 polymorphisms are associated with rheumatoid arthritis risk. [Copyright &y& Elsevier]

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98% due to widespread metastatic disease. A better understanding of the molecular mechanism of pancreatic cancer is beneficial for the development of novel approaches for early detection and monitoring of pancreatic cancer. We aim to comprehensively identify the gene expression profile in pancreatic cancer and explore the molecular pathway of pancreatic cancer disorder. Using GSE15471 datasets downloaded from Gene Expression Omnibus data, we first screened the differentially expressed genes in pancreatic cancer using packages in R language. The key pathways of differentially expressed genes were investigated with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and synergetic network construction based on weighted Jaccard index. A total of 13,211 differentially expressed genes were identified, and they were enriched in several pathways, such as mitogen-activated protein kinase (MAPK) signaling pathway, transforming growth factor (TGF)-beta signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, and calcium signaling pathway, as well as cell cycle, focal adhesion, complement and coagulation cascades, and leukocyte transendothelial migration. Synergetic pathway network analysis revealed that cytokine-cytokine receptor interaction pathway, calcium signaling pathway, and focal adhesion pathway were three important pathways in the development of pancreatic cancer. The method introduced here is helpful to screen the key pathways for controlling pancreatic cancer progression and provide potential therapeutic targets in the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Myogenic differentiation plays an important role in muscle regeneration and is regulated by two transcription factor families, MRFs and MEF2, which induce differentiation of myoblasts through expression of the muscle-specific gene, myogenin. In addition, many intracellular signaling pathways are also involved in myogenic differentiation, including p38 MAPK, ERK/MAPK and PI3K/AKT. The JAK-STAT pathway is activated by various cytokines and positively or negatively regulates the differentiation of myoblasts. JAK1 plays a notable role in proliferation; whereas, JAK2 and JAK3 function mainly in differentiation. The STATs, molecules downstream of JAK, regulate myogenesis. With JAK1, STAT1 promotes proliferation, while STAT3 has a dual effect on proliferation and differentiation. The JAK-STAT negative regulator, SOCS, is also associated with myogenesis; although, its role is controversial. In this review, we will discuss the role of the JAK-STAT pathway on myogenic differentiation. [ABSTRACT FROM AUTHOR]

The generation of germline gene mutations in mice has been an invaluable tool for experimental biology. However, studying immune responses that develop in the absence of a specific protein that could alter thymic selection complicates experimental interpretations. We observed that CD8+ T cells from Stat6-/- mice displayed "autoreactivity" to STAT6- expressing cells, associated with specific STAT6 peptides binding to MHC class I molecules. These results suggest caution in interpreting experiments where STAT6-expressing cells are transferred into Stat6-/- mice, or where adoptive transfer of Stat6-/- lymphocytes is performed. Our results further highlight additional considerations when studying immune responses involving cell transfer into gene-deficient mice. [ABSTRACT FROM AUTHOR]

During recent years a number of primary immunodeficiencies resulting from impaired function of JAK-STAT molecules have been described. One of these is the Hyper-IgE syndrome (HIES) characterized by elevated IgE levels, eczema, recurrent staphylococcal skin and pulmonary infections and pleiotropic somatic manifestations. In 2007 the genetic basis of HIES was revealed by identification of dominant negative STAT3 mutations in HIES patients. Subsequently impaired function of Tyk2 and DOCK8 have been implicated in milder forms of HIES. Since STAT3 acts as a central transcription factor downstream of multiple cytokine and growth factor receptors and thus regulates antimicrobial responses and cell survival, impaired STAT3 function results in immunodeficiency and in some cases tumorigenesis. However, as the immunological and molecular basis of HIES is being unraveled, important biological and immunological insight into JAK-STAT signaling is emerging that may have implications for our understanding of the pathogenesis and clinical management of patients with HIES. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Mucins play a critical role in the malignancy of various tumors and have been identified as diagnostic markers and as attractive therapeutic targets. However, the role of mucin (MUC) 20 in endometrial cancer (EC) is still unknown. Methods: The relationship between MUC20 expression and clinical characteristics of EC was analyzed in 97 EC tumors and 16 normal tissues by immunohistochemistry. Effects of MUC20 on EC cells, HEC-1A and RL95-2, were examined by in vitro cell growth, migration, and invasion assays, as well as in vivo tumor growth in SCID mouse model. Western blotting was performed to analyze signaling pathways modulated by MUC20. Results: MUC20 expression was significantly higher in EC tumors compared with the normal tissue. High levels of MUC20 expression in EC tumors were correlated with an unfavorable histologic subtype. Furthermore, MUC20 was an independent prognostic factor for poor survival as evaluated by multivariate analyses. Overexpression of MUC20 in EC cells significantly enhanced cell growth, migration, and invasion, as well as tumor growth in vivo. The MUC20-enhanced invasive behavior was significantly blocked by erlotinib, an EGFR inhibitor. Moreover, MUC20 overexpression enhanced EGF-mediated migration and invasion, suggesting a critical role of EGFR in MUC20-mediated effects. We found that MUC20 overexpression could enhance EGF-induced phosphorylation of EGFR and STAT3. Inhibition of the STAT3 activity by its inhibitor Stattic significantly suppressed the MUC20-enhanced invasive behavior. Conclusions: MUC20 is novel prognostic factor for EC and its overexpression enhances EGF-triggered invasive behavior through activation of EGFR–STAT3 pathway. [Copyright &y& Elsevier]

Abstract: Leptin overexpression contributes to the tumorigenesis of ovarian cancer. However, the functional mechanism and effects remain unclear. The aberrant expression of tumor-related microRNAs may play an important role in the development of cancer. In this report, we demonstrate that crosstalk between leptin and microRNA-182 and microRNA-96 affects the transformation and proliferation of ovarian cancer cells. Our results showed that leptin enhanced the colony formation of ovarian cancer cells in soft agar. A water-soluble tetrazolium salts assay revealed that leptin promoted ovarian cancer cell (SKOV3 and A2780 cells) proliferation in a time- and dose-dependent manner. The growth effects of leptin on ovarian cancer cells were mediated via the reduced expression of forkhead box O3 and its downstream targets p27 and Bim. We demonstrated that leptin upregulated miRNAs that target forkhead box O3 via luciferase reporter assay. Further examination indicated that only the inhibition of microRNA-182 and/or microRNA-96 rescued the expression of forkhead box O3 inhibited by leptin, and their mimics promoted the proliferation of ovarian cancer cells. Moreover, the signal transducer and activator of transcription 5 pathway, but not the signal transducer and activator of transcription 3 pathway, was implicated in the leptin-mediated expression of microRNA-182 and microRNA-96. In conclusion, our findings suggest that the upregulation of microRNA-182 and microRNA-96 targeting forkhead box O3 plays a significant role in the pro-proliferation effect of leptin on ovarian cancer cells, which might provide preliminary experimental clues for the development of new therapies against ovarian cancer. [Copyright &y& Elsevier]

Abstract: Objective: Signal-transducer and activator of transcription protein 3 (STAT3) gene encodes a transducer and transcription factor that plays an important role in many cellular processes such as cell growth, apoptosis and immune response. Several STAT3 genetic variants have been associated to different autoimmune diseases. Our aim was to reveal the possible STAT3 influence in other immune-mediated diseases such as psoriatic arthritis (PsA) and Behcet disease (BD). Methods: The STAT3 rs744166 and rs2293152 polymorphisms were genotyped using predesigned TaqMan® assays in a total of 335 PsA patients, 217 BD patients, and 1844 ethnically matched healthy controls of Spanish Caucasian origin. Results: A statistically significant association of the STAT3 rs744166∗G allele with PsA was observed (P-value=1.36×10−3, OR 1.35). The detected effect was more evident when the rs744166∗GG homozygote frequencies were compared between PsA patients and controls (genotype P-value=9.77×10−5, OR 1.82). In contrast, the allele and genotypic distributions of rs744166 polymorphism showed no significant differences between patients with BD and control subjects (allelic P-value=0.80, OR 1.03). Additionally, no evidence of association was detected between the rs2293152 genetic variant and both studied diseases. Conclusion: Our results suggest for the first time that the STAT3 gene might be involved in PsA but not in Behcet’s disease predisposition. [Copyright &y& Elsevier]

Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy. [ABSTRACT FROM AUTHOR]

Cytokine signals are essential for generating a robust and specialized immune response. These signals are typically transmitted via canonical STAT homodimers. However, the number of STAT molecules utilized by cytokine signaling cascades within immune cells are limited, and so the mechanism used to deliver complex signals remains elusive. Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor and may play an important role in dictating the targets of specific cytokine signaling. In this review, we discuss our current understanding of the prevalence of STAT heterodimers, how they are formed and what their physiologic role may be in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis. [Copyright &y& Elsevier]

Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoprollferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequenc-ing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are pres-ent in both T and NK diseases: approxi-mately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pat-tern of STAT3 activation and gene deregu-lation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, Indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoprolif-erative disorders. Treatment with STAT3 Inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a simi-lar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations Involving T and NK cells from reactive expansions. [ABSTRACT FROM AUTHOR]

Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malignant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy. [ABSTRACT FROM AUTHOR]

Common polymorphisms within the FTO (fat mass and obesity-associated) gene correlate with increased BMI (body mass index) and a rising risk of Type 2 diabetes. FTO is highly expressed in the brain but has also been detected in peripheral tissues, including the endocrine pancreas, although its function there is unclear. The aim of the present study was to investigate the role of FTO protein in pancreatic β-cells using a conditional expression system developed in INS-1 cells. INS-1 cells were stably transfected with FTO−HA (haemagluttinin) incorporated under the control of a tetracycline-inducible promoter. Induction of FTO protein resulted in localization of the tagged protein to the nucleus. The level of FTO−HA protein achieved in transfected cells was tightly regulated, and experiments with selective inhibitors revealed that FTO−HA is rapidly degraded via the ubiquitin/proteasome pathway. The nuclear localization was not altered by proteasome inhibitors, although following treatment with PYR-41, an inhibitor of ubiquitination, some of the protein adopted a perinuclear localization. Unexpectedly, modestly increased expression of FTO−HA selectively enhanced the first phase of insulin secretion when INS-1 monolayers or pseudoislets were stimulated with 20 mMglucose, whereas the second phase remained unchanged. The mechanism responsible for the potentiation of glucose-induced insulin secretion is unclear; however, further experiments revealed that it did not involve an increase in insulin biosynthesis or any changes in STAT3 (signal transducer and activator of transcription 3) expression. Taken together, these results suggest that the FTO protein may play a hitherto unrecognized role in the control of first-phase insulin secretion in pancreatic β-cells. [ABSTRACT FROM AUTHOR]

The article discusses research on advances in the identification and functional characterization of new activators and regulators of innate immune signaling pathways.

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching. STAT3 activates distinct transcriptional programmes within cancer cells. In this study, the authors find that, in glioma, a STAT3-mediated expression signature can stratify patients for targeted precision therapy. [ABSTRACT FROM AUTHOR]

Lung cancer remains a challenging disease. It is responsible for the high cancer mortality rates in the US and worldwide. Elucidation of the molecular mechanisms operative in lung cancer is an important first step in developing effective therapies. Accumulating evidence over the last 2 decades suggests a critical role for Signal Transducer and Activator of Transcription 3 (STAT3) as a point of convergence for various signaling pathways that are dysregulated in the disease. In this review, we discuss possible molecular mechanisms involving STAT3 in lung tumorigenesis based on recent literature. We consider possible roles of STAT3 in cancer cell proliferation and survival, in the tumor immune environment, and in epigenetic regulation and interaction of STAT3 with other transcription factors. We also discuss the potential role of STAT3 in tumor suppression, which complicates strategies of targeting STAT3 in cancer therapy. [ABSTRACT FROM PUBLISHER]