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

Sang A. Park, Min Jin Kim, So Yeon Park, Jung Shin Kim, Woosung Lim, Jeong Seok Nam, Yhun Yhong Sheen

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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.

Original languageEnglish
Article number16492
JournalScientific Reports
StatePublished - 9 Nov 2015

Bibliographical note

Funding Information:
This work was supported by HI14C3313 from the Korea Health Industry Development Institute (KHIDI) of the Republic of Korea. We thank Dae-Kee Kim (Ewha Womans University, Seoul, Korea) for providing EW-7197, LY-2157299, and SB-505124. We also thank Min-Kyung Park (Ewha Womans University, Seoul, Korea) for the technical and administrative support.


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