STAT proteins – Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver

Gao, Bin; Wang, Hua; Lafdil, Fouad; Feng, Dechun

doi:10.1016/j.jhep.2012.01.029

Cited by 153 publications

(129 citation statements)

References 134 publications

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“…Furthermore, SHP-1 phosphatase-directed therapy (e.g., SC-1) might be a previously unidentified strategy for the discovery of antifibrotic drugs. STAT3 activation has been detected in several human liver diseases, and STAT3 signaling is involved in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis (8,9). The role of STAT3 in liver inflammation and fibrosis is cell type-specific and model-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying mechanisms of the antifibrogenic effects remain unclear. The signal transducer and activator of transcription 3 (STAT3) is a transcription factor associated with liver injury, inflammation, and regeneration (8,9). Several studies have shown that interleukin-6 (IL-6) activates STAT3 in HSCs and promotes their survival, proliferation, and activation, thus contributing to liver fibrogenesis (8,10).…”

mentioning

confidence: 99%

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Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.hepatic stellate cell | STAT3 | SHP-1 | hepatitis B | liver fibrosis

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…STAT proteins act as a key signaling cascade mediating cytokine receptor-derived signals, and activation of STAT members serves to transduce signals through the cytoplasm and to function as transcription factors in the nucleus (Miklossy et al, 2013). Among the six distinct STAT members (ie, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6) (Yu et al, 2009), STAT3 is thought to be a mediator of inflammation (Levy and Lee, 2002), as both IL-6 and TNF have been shown to activate STAT3; IL-6 mediates its effects through the STAT3 pathway; and STAT3 competes with the transcription factor NF-κB (Gao et al, 2012). STAT1 is linked to interferon (IFN) signaling, and STAT5 is linked to IL-2 (Shuai and Liu, 2003).…”

Section: Experimental Sleep Deprivation and Cellular Dynamics And Tramentioning

confidence: 99%

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

Irwin

Opp

2016

Neuropsychopharmacol

364

268

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Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder. This review and overview provides an integrated understanding of the reciprocal relationships between sleep and the innate immune system and considers the role of sleep in the nocturnal regulation of the inflammatory biology dynamics; the impact of insomnia complaints, extremes of sleep duration, and experimental sleep deprivation on genomic, cellular, and systemic markers of inflammation; and the influence of sleep complaints and insomnia on inflammaging and molecular processes of cellular aging. Clinical implications of this research include discussion of the contribution of sleep disturbance to depression and especially inflammation-related depressive symptoms. Reciprocal action of inflammatory mediators on the homeostatic regulation of sleep continuity and sleep macrostructure, and the potential of interventions that target insomnia to reverse inflammation, are also reviewed. Together, interactions between sleep and inflammatory biology mechanisms underscore the implications of sleep disturbance for inflammatory disease risk, and provide a map to guide the development of treatments that modulate inflammation, improve sleep, and promote sleep health.

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“…STAT1 has previously been considered to function as a tumor suppressor to induce cell-cycle arrest and apoptosis in various types of cancers (30,31). To determine how STAT1 contributes to cell growth and survival in SPEC, various in vitro functional assays were performed using SPAC-1L cells following manipulation of STAT1 activity.…”

Section: Stat1 Functions As a Tumor Prosurvival And Proprogression Gementioning

confidence: 99%

STAT1 Drives Tumor Progression in Serous Papillary Endometrial Cancer

et al. 2014

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Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers, but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a "SPEC signature" as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7, as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together, our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a prosurvival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease. Cancer Res; 74(22); 6519-30. Ó2014 AACR.

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STAT proteins – Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver

Cited by 153 publications

References 134 publications

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

STAT1 Drives Tumor Progression in Serous Papillary Endometrial Cancer

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