STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib

Deng, Yan Ru; Di, Hong J.; Tsuneyama, Koichi; Yang, Wei; Wang, Yin Hu; Lu, Fang; Liu, Cheng Hai; Liu, Ping; He, Xiaosong; Diehl, Anna Mae; Gershwin, M. Eric; Lian, Zhe Xiong

doi:10.1016/j.jaut.2013.07.008

Cited by 87 publications

(76 citation statements)

References 43 publications

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“…Although sorafenib suppresses HSC by p-STAT3 inhibition in our study, a recent study suggested that sorafenib suppressed TGF-β1 induced epithelial-mesenchymal transition and apoptosis of hepatocytes, and also inhibited TGF-β1-induced STAT3 phosphorylation (23). Recently, Deng et al demonstrated that STAT3 in hepatocytes was critical for sorafenib-mediated protection against liver fibrosis, by Kupffer cellderived IL-6-dependent p-STAT3 up-regulation (24). In our study, we consistently confirmed the antifibrotic effect of sorafenib and further verified that sorafenib inhibited the STAT3 pathway and downstream cyclin D1 and Mcl-1 expression, which are involved in the cell-cycle regulation and apoptosis (25).…”

Section: Discussioncontrasting

confidence: 56%

“…Deng et al showed the nuclear translocation of STAT3 in hepatocytes after sorafenib treatment; however, after thioacetamide induction, we found nuclear p-STAT3 overexpressed largely in HSC and reduced by sorafenib. One possible explanation of these findings is Columns, mean; bars, SE (n = 3) *P < 0.05, **P < 0.01, ***P < 0.001. a time-dependent hepatic p-STAT3 inhibition and followed by activation during fibrogenesis, indicating a dynamic regulation by IL-6 from Kupffer cells (24). These results highlight the impact of the different cell types on the STAT3-dependent effects of sorafenib and STAT3 may be a key player in liver fibrosis.…”

Section: Discussionmentioning

confidence: 67%

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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: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 67%

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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“…Thus, Cthrc1 and phospho-Smad3 constitute a negative feedback loop in the TGF-β pathway [25]. Negative feedback loops in the TGF-β pathway are a naturally occurring phenomena.…”

Section: 1 Discussionmentioning

confidence: 99%

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

Bian

Miao

Zhong

et al. 2015

Journal of Autoimmunity

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Collagen triple helix repeat containing-1 (Cthrc1) is a documented specific inhibitor of TGF-β signaling. Based on this observation, we developed the hypothesis that knocking in/knocking out the Cthrc1 gene in murine models of cholestasis would alter the natural history of cholestatic fibrosis. To study this thesis, we studied two murine models of fibrosis, first, common bile duct ligation (CBDL) and second, feeding of 3, 5-diethoxy-carbonyl-1, 4-dihydrocollidine (DDC). In both models, we administered well-defined adenoviral vectors that expressed either Cthrc1 or, alternatively, a short hairpin RNA (shRNA)-targeting Cthrc1 either before or after establishment of fibrosis. Importantly, when Cthrc1 gene expression was enhanced, we noted a significant improvement of hepatic fibrosis, both microscopically and by analysis of fibrotic gene expression. In contrast, when Cthrc1 gene expression was deleted, there was a significant exacerbation of fibrosis. To identify the mechanism of action of these significant effects produced by knocking in/knocking out Cthrc gene expression, we thence studied the interaction of Cthrc1 gene expression using hepatic stellate cells (HSCs) and human LX-2 cells. Importantly, we demonstrate that Cthrc1 is induced by TGF-β1 via phospho-Smad3 binding to the promoter with subsequent transcription activation. In addition, we demonstrate that Cthrc1 inhibits TGF-β signaling by accelerating degradation of phospho-Smad3 through a proteosomal pathway. Importantly, the anti-fibrotic effects can be recapitulated with a truncated fragment of Cthrc1. In conclusion, our findings uncover a critical negative feedback regulatory loop in which TGF-β1 induces Cthrc1, which can attenuate fibrosis by accelerating degradation of phospho-Smad3.

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“…PTPRO expression attenuates STAT3 activity, which in hepatocytes plays a protective role in preventing liver fibrosis [44,45]. Research has also found that up-regulation of STAT3 phosphorylation is dependent on Kupffer-cell-derived IL-6 secretion [46]. PTPRO expression in vivo may also be an indirect cooperating with a direct mechanism in HSC activation and progression of liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

Zhang

Tan²,

Wang³

et al. 2015

Cell Physiol Biochem

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Background/Aims: PTPRO (protein tyrosine phosphatase, receptor type O) is implicated in diverse physiological and pathological processes in cancer and hepatic ischemia/reperfusion injury, although little is known about its role in hepatic fibrosis. Methods: Here, by using genetically deficient mice, we reported that PTPRO knockout (PTPRO^-/-) significantly attenuated liver injury, release of inflammatory factors, tissue remodeling, and liver fibrosis in two experimental mouse models of fibrogenesis induced by bile-duct ligation or carbon tetrachloride administration. Results: However, we proved that PTPRO expression was strongly downregulated in clinical and experimental liver fibrosis specimens. Further investigations revealed that stimulation of primary hepatic stellate cells (HSCs) and hepatocytes with specific activator platelet-derived growth factor (PDGF)-BB increased PTPRO transcription in HSCs but had the opposite effect in primary hepatocytes. More importantly, synthetic short hairpin RNA targeting PTPRO significantly neutralized PDGF-BB-induced HSC proliferation and myofibroblast marker expression through downregulated phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Conclusion: These observations confirm that PTPRO plays a critical role in liver fibrogenesis by affecting PDGF signaling in HSC activation and might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

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STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib

Cited by 87 publications

References 43 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

Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

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