Abstract:
:Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC. This study was undertaken to gain the proof of concept of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197 as a potent anti-cancer therapy for HCC. We identified tissue inhibitors of metalloproteinases-1 (TIMP-1) as one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-β-mediated crosstalk between HSCs and HCC cells. TGF-β signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-β signaling using EW-7197 significantly attenuated the progression and intrahepatic metastasis of HCC in an SK-HEP1-Luc orthotopic-xenograft mouse model. In addition, EW-7197 inhibited TGF-β-stimulated TIMP-1 secretion by HSCs as well as the TIMP-1-induced proliferation, motility, and survival of HCC cells. Further, EW-7197 interrupted TGF-β-mediated epithelial-to-mesenchymal transition and Akt signaling, leading to significant reductions in the motility and anchorage-independent growth of HCC cells. In conclusion, we found that TIMP-1 mediates TGF-β-regulated crosstalk between HSCs and HCC cells via FAK signaling. In addition, EW-7197 demonstrates potent in vivo anti-cancer therapeutic activity and may be a potential new anti-cancer drug of choice to treat patients with liver cancer.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Park SA,Kim MJ,Park SY,Kim JS,Lim W,Nam JS,Yhong Sheen Ydoi
10.1038/srep16492subject
Has Abstractpub_date
2015-11-09 00:00:00pages
16492issn
2045-2322pii
srep16492journal_volume
5pub_type
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journal_title:Scientific reports
pub_type: 杂志文章
doi:10.1038/s41598-019-47174-9
更新日期:2019-07-24 00:00:00
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abstract::HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding ...
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2017-01-11 00:00:00
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pub_type: 杂志文章
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更新日期:2015-11-10 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章,meta分析
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pub_type: 已发布勘误
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2015-09-22 00:00:00
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pub_type: 杂志文章
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更新日期:2017-03-15 00:00:00
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pub_type: 杂志文章
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journal_title:Scientific reports
pub_type: 杂志文章
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pub_type: 杂志文章
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