Unphosphorylated STAT3 regulates the antiproliferative, antiviral, and gene-inducing actions of type I interferons.

Type I interferon (IFNα/β) induces antiviral and antiproliferative responses in cells through the induction of IFN-stimulated genes (ISGs). Although the roles of IFN-activated STAT1 and STAT2 in the IFN response are well described, the function of STAT3 is poorly characterized. We investigated the role of STAT3 in the biological response to IFNα/β in mouse embryonic fibroblasts (MEFs) with a germ line deletion of STAT3.

MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis.

MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival.

Detection of Exosomal miRNAs in the Plasma of Melanoma Patients.

MicroRNAs (miRNAs) are a class of 22-25 nucleotide RNAs that control gene expression at the post-transcriptional level. MiRNAs have potential as cancer biomarkers. Melanoma is a highly aggressive form of skin cancer accounting for almost 4% of cancers among men and women, and ~80% of skin cancer-related deaths in the US.

The Type I IFN-Induced miRNA, miR-21.

The interferon (IFN) family of cytokines not only has antiviral properties at various steps in the viral replication cycle, but also anticancer activity through multiple pathways that include inhibiting cell proliferation, regulating cellular responses to inducers of apoptosis and modulating angiogenesis and the immune system. IFNs are known to induce their biological activity through the induction of protein encoding IFN-stimulated genes. However, recent studies have established that IFNs also induce the expression of microRNAs (miRNAs), which are small endogenous non-coding RNAs that suppress gene expression at the post-transcriptional level.

The Role of miR-21 in Cancer.

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that suppress gene expression at the post-transcriptional level. In the past decade, miRNAs have been extensively studied in a number of different human cancers. MiRNAs have been identified to act both as oncogenes and as tumor suppressors.

The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis.

The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene.

Identification of imidazoquinoline derivatives as potent antiglioma agents.

Glioblastoma Multiforme (GBM) is a highly fatal disease and new chemotherapeutic agents are desperately needed to treat GBM patients. With the aim of identifying new antiglioma agents we screened the UC DDC library for compounds structurally related to the antiglioma lead molecule compound 1 (SP-6-27) and clinically used compound 2 (Azixa). We identified imidazoquinoline analog 3 (S-94403) as initial hit from the first screen which included the different heterocyclic sets of 15 compounds.

An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV.

MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).

Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue.

Isolation of circulating microRNAs from microvesicles found in human plasma.

Intact miRNAs can be isolated from the circulation in significant quantities despite the presence of extremely high levels of RNase activity. The remarkable stability of circulating miRNAs makes them excellent candidates for biomarkers in diagnostic applications as well as therapeutic targets in a variety of disease states including melanoma. Circulating RNA molecules are resistant to degradation by RNases because they are encapsulated in membrane-bound microvesicles.

Altered transcriptome signature of phenotypically normal skin fibroblasts heterozygous for CDKN2A in familial melanoma: relevance to early intervention.

Familial melanoma (FM) is a dominantly heritable cancer that is associated with mutations in the tumor suppressor CDKN2A/p16. In FM, a single inherited "hit" occurs in every somatic cell, enabling interrogation of cultured normal skin fibroblasts (SFs) from FM gene carriers as surrogates for the cell of tumor origin, namely the melanocyte. We compared the gene expression profile of SFs from FM individuals with two distinct CDKN2A/p16 mutations (V126D-p16 and R87P-p16) with the gene expression profile of SFs from age-matched individuals without p16 mutations and with no family history of melanoma.

Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.

Unlabelled: Chemokines and inflammatory cytokines are key regulators of immunity and inflammation during viral infections. Hepatitis C virus (HCV) is a hepatotropic RNA virus frequently associated with chronic liver inflammation and hepatocellular carcinoma. Intrahepatic levels of chemokines and cytokines are elevated in chronic HCV infections, but the underlying mechanisms remain unclear.

MicroRNA miR-21 regulates the metastatic behavior of B16 melanoma cells.

MicroRNA-21 (miR-21) is overexpressed in many human tumors and has been linked to various cellular processes altered in cancer. miR-21 is also up-regulated by a number of inflammatory agents, including IFN, which is of particular interest considering the close relationship between inflammation and cancer. Because miR-21 appears to be overexpressed in human melanoma, we examined the role of miR-21 in cancer development and metastasis in B16 mouse melanoma cells.

The role of TRAF2 binding to the type I interferon receptor in alternative NF kappaB activation and antiviral response.

Type I interferons (IFNs) play critical roles in the host defense by modulating gene expression through the IFN-dependent activation of STAT and NFkappaB transcription factors. Previous studies established that IFN activates NFkappaB through a classical NFkappaB pathway that results in IkappaBalpha degradation and formation of p50-containing NFkappaB complexes, as well as an alternative pathway that involves NFkappaB-inducing kinase and TRAF2, which results in the formation of p52-containing NFkappaB complexes. In this study, we examined the interaction of TRAF proteins with the type I IFN receptor.

Non-conventional signal transduction by type 1 interferons: the NF-kappaB pathway.

Type I interferons (IFNs) regulate diverse cellular functions by modulating the expression of IFN-stimulated genes (ISGs) through the activation of the well established signal transduction pathway of the Janus Kinase (JAK) and signal transducers and activators of transcription (STAT) proteins. Although the JAK-STAT signal transduction pathway is critical in mediating IFN's antiviral and antiproliferative activities, other signaling pathways are activated by IFNs and regulate cellular response to IFN. The NF-kappaB transcription factor regulates the expression of genes involved in cell survival and immune responses.

Identification of CXCL11 as a STAT3-dependent gene induced by IFN.

IFNs selectively regulate gene expression through several signaling pathways. The present study explored the involvement of STAT3 in the IFN-induced expression of the gene encoding the CXCL11 chemokine. The CXCL11 gene was induced in IFN-sensitive Daudi cells, but not in an IFN-resistant DRST3 subline with a defective STAT3 signaling pathway.

Role of nuclear factor-kappaB in the antiviral action of interferon and interferon-regulated gene expression.

Interferons (IFNs) play critical roles in host defense by modulating the expression of various genes via tyrosine phosphorylation of STAT transcription factors. IFN-alpha/beta activates another important transcription factor, nuclear factor-kappaB (NF-kappaB), but its role in IFN-mediated activity is poorly understood. Sensitivity to the antiviral and gene-inducing effects of IFN was examined in normal fibroblasts and in NF-kappaB knockout fibroblasts from p50- and p65-null mice.