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TIMP-1 mediates TGF-beta-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling

Title
TIMP-1 mediates TGF-beta-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling
Authors
Park, Sang-AKim, Min-JinPark, So-YeonKim, Jung-ShinLim, WoosungNam, Jeong-SeokSheen, Yhun Yhong
Ewha Authors
신윤용임우성
SCOPUS Author ID
신윤용scopus; 임우성scopus
Issue Date
2015
Journal Title
SCIENTIFIC REPORTS
ISSN
2045-2322JCR Link
Citation
vol. 5
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Transforming growth factor-beta (TGF-beta) 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-beta 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-beta-mediated crosstalk between HSCs and HCC cells. TGF-beta signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-beta 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-beta-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-beta-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-beta-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 anticancer drug of choice to treat patients with liver cancer.
DOI
10.1038/srep16492
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약학대학 > 약학과 > Journal papers
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