Abstract
Periostin is a critical extracellular regulator in the pathogenesis of liver disorders such as hepatosteatosis, non-alcoholic steatohepatitis, inflammation, and fibrosis. Periostin is also involved in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms of periostin in hepatic stellate cell (HSC) activation and tumor cell proliferation in the pathogenesis of HCC remain largely unknown. We demonstrate that periostin is markedly upregulated in diethylnitrosamine (DEN)-induced mouse HCC tissues and that periostin knockout impairs DEN-induced HCC development. Periostin is predominantly derived from activated HSCs and periostin deficiency in HSCs impairs HSC activation and inhibits HSC-promoted HCC cell proliferation in vitro and tumor growth in vivo. Mechanistically, periostin promotes HSC activation through the integrin-FAK-STAT3-periostin pathway and augments HCC cell proliferation by activating ERK. There are positive correlations between periostin and HSC activation and cell proliferation in HCC clinical samples. Collectively, our findings demonstrate that HSC-derived periostin promotes HCC development by enhancing HSC activation through an autocrine periostin-integrin-FAK-STAT3-periostin circuit and by augmenting HCC cell proliferation via the ERK pathway in a paracrine manner. Thus, periostin is a multifaceted extracellular regulator in the development of HCC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.