Project description:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. Our findings reveal a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
Project description:Although the oncogenic signalings driven by amplification and mutations of EGF receptor (EGFR) gene play a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59), acting as a new downstream effector of EGFR signaling, regulates STAT3 activation in glioblastoma. EGFR signaling leads to TRIM59 upregulation through SOX9 that results in enhancing TRIM59 interaction with STAT3 in nucleus, and inhibiting STAT3 association with TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP), thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumorigenesis of GBM cells. Moreover, evaluation of GBM patient samples reveals an association among EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR-STAT3 signaling and a potential therapeutic target for GBM patients with EGFR activation.
Project description:In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma. GBM6 cells were continuously maintained as subcutaneous xenografts in NSG mice, and monolayer and CSC cultures were derived from freshly harvested tumor tissue. A total of 6 samples were subjected to microarray analysis, with three biological replicates for each experimental condition.
Project description:Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response towards an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y705. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.
Project description:The capacity of embryonic stem cells to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining embryonic stem cells identity. However the underlying mechanism how Stat3 directs differentiation is still not completely understood. Here we show that Stat3 positively regulates gene expression of methyltransferase like protein 8 (Mettl8) in mouse ES cells. We found that Mettl8 is dispensable for pluripotency but affects ESCs differentiation. Subsequently we discovered that Mettl8 interacts with Mapkbp1’s mRNA, which is an intermediate factor in JNK signaling, and inhibits the translation of the mRNA. Thereby, Mettl8 prohibits the activation of JNK signaling and enhances the differentiation of mouse ESCs. Collectively, our study uncovers a Stat3 target Mettl8 which regulates mouse ESCs differentiation via JNK signaling.
Project description:We identified a novel mechanism by which IL-6/STAT3 signaling up-regulates CD133 expression and promotes HCC progression. STAT3 activation upregulates the expression of CD133 during liver carcinogenesis. Targeting STAT3-mediated CD133 overexpression may represent a promising therapeutic strategy for HCC patients via eradicating the liver tumor microenviornment. To develop novel cancer therapeutic strategies by identification of signaling pathways or biomarkers and understanding their functions on cancer stem cell biology, we determined CD133 expression and STAT3 activation with tumor microenvironment in HCC patient tissues. The relation of STAT3 activation and CD133 expression was investigated by luciferase assay, shRNA knock-down, and chromatin immunoprecipitation assay in HCC cells, and in vivo xenograft model.