Periostin-IHH feedforward loop promotes hepatocellular carcinoma development by enhancing hepatic fibrosis and tumor cell proliferation.

The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and tumor growth in the progression of HCC. Here we demonstrate that periostin deficiency impairs HCC development and decreases tissue stiffness of liver tumors in DEN/CCl4-treated mice. Increased matrix stiffness enhanced periostin expression in hepatic stellate cells (HSCs). The combination of periostin and increased stiffness synergistically promoted HCC cell proliferation in vitro. Moreover, periostin deficiency in HSCs impaired both HSC-promoted and stiffness-increased HCC cell proliferation in vivo. We further demonstrated that periostin promotes Indian hedgehog (IHH) expression in HCC cells through the integrin-PYK2-TAZ pathway. Conversely, IHH increased the expression of periostin in HSCs via GLI2. Periostin expression positively correlates with fibrotic features and IHH signaling in clinical HCC tissues. Collectively, these findings indicate that periostin and IHH cooperatively contribute to the development of HCC by regulating the tumor-stroma crosstalk via the periostin-integrin-PYK2-TAZ-IHH pathway in tumor cells and IHH-GLI2-periostin signaling in HSCs.