Park Sang-A, Kim Min-Jin, Park So-Yeon, Kim Jung-Shin, Lim Woosung, Nam Jeong-Seok, Yhong Sheen Yhun
College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Department of Surgery, Ewha Womans University School of Medicine, Seoul, South Korea.
Sci Rep. 2015 Nov 9;5:16492. doi: 10.1038/srep16492.
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.
转化生长因子-β（TGF-β）信号通路在肝癌的进展和转移中起关键作用。本研究旨在验证TGF-β I型受体激酶小分子抑制剂EW-7197作为肝癌有效抗癌疗法的概念。我们确定金属蛋白酶组织抑制剂-1（TIMP-1）是肝星状细胞（HSCs）分泌的蛋白之一，也是TGF-β介导的HSCs与肝癌细胞间串扰的关键介质。TGF-β信号通路导致TIMP-1表达增加，TIMP-1通过与CD63相互作用激活粘着斑激酶（FAK）信号通路。在SK-HEP1-Luc原位异种移植小鼠模型中，使用EW-7197抑制TGF-β信号通路可显著减弱肝癌的进展和肝内转移。此外，EW-7197抑制HSCs分泌TGF-β刺激的TIMP-1以及TIMP-1诱导的肝癌细胞增殖、迁移和存活。此外，EW-7197阻断TGF-β介导的上皮-间质转化和Akt信号通路，导致肝癌细胞迁移和非锚定依赖性生长显著降低。总之，我们发现TIMP-1通过FAK信号通路介导TGF-β调节的HSCs与肝癌细胞间串扰。此外，EW-7197在体内显示出强大的抗癌治疗活性，可能是治疗肝癌患者的潜在新型抗癌药物选择。
