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

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

doi:10.1038/srep16492

Sang-A Park, Woosung Lim + Show 5 more

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https://doi.org/10.1038/srep16492

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Journal: Scientific Reports	Publication Date: Nov 9, 2015
Citations: 51	License type: CC BY 4.0

Affiliation: Ewha Womans University, Gachon University

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.

Highlights

Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of Hepatocellular carcinoma (HCC)
transforming growth factor-β (TGF-β) signaling appears to be a potential target for HCC treatment, and the direct inhibition of ALK5 might be an attractive approach to prevent detrimental tumor progression due to TGF-β signaling
We report for the first time that EW-7197, a selective ALK5 inhibitor, blocks the production of tissue inhibitor of metalloproteinases-1 (TIMP-1) in TGF-β 1-activated hepatic stellate cells (HSCs), which interrupts communication between HSCs and HCC cells, and inhibits the progression and intrahepatic metastasis of HCC

Summary

Introduction

Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC. We found that TIMP-1 mediates TGF-β-regulated crosstalk between HSCs and HCC cells via FAK signaling. To determine the TGF-β -regulated molecular link between HSCs and HCC, we screened for candidate factors secreted from activated HSCs. We identified tissue inhibitor of metalloproteinases-1 (TIMP-1) as a potent protein secreted by HSCs that advances the progression and metastasis of HCC. We further demonstrated that TIMP-1 mediated TGF-β -regulated crosstalk between HSCs and HCC cells through FAK signaling. Based on these data, TGF-β signaling is a potential target for the treatment of HCC, and the direct inhibition of TGF-β signaling has been demonstrated to have therapeutic effects on HCC both in vitro and in vivo[18,22,23,24]. We show that EW-7197 inhibits TGF-β signaling to exert therapeutic effects on HCC progression

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