Periostin Promotes DEN-Induced Liver Cancer In Mice By Increasing HSC Activation And Cancer Cell Proliferation

Periostin(Postn) is a critical extracellular regulator in the pathogenesis of distinct liver disorders such as hepatosteatosis,nonalcoholic steatohepatitis,inflammation,fibrosis and liver metastasis of other cancers.However,the functions of periostin in the pathogenesis of hepatocellular carcinoma(HCC)and the underlying mechanisms remain largely unknown.The presented study demonstrates that periostin is markedly upregulated in diethylnitrosamine(DEN)induced mouse HCC tissues.Knockout of periostin significantly impairs DEN-induced HCC development in mice.We further found that periostin is predominantly derived from activated hepatic stellate cells(HSCs)and that periostin deficiency in HSCs impairs HSC-promoted HCC cell proliferation in vitro and tumor growth in vivo.Mechanistically,periostin promotes HSC activation through integrin-FAK-STAT3-periostin signaling pathway.Meanwhile,periostin augments the proliferation of HCC cells by activating ERK signaling pathway.Moreover,in HCC clinical samples,periostin is upregulated and there is a positive correlation between periostin expression and HSC activation markers(α-SMA and Collal)and cancer cell proliferation marker(Ki67).Conclusion:Our findings demonstrate that HSC-derived periostin promotes the development of HCC by enhancing HSC activation through autocrine periostin-integrin-FAK-STAT3-periostin circuit and augmenting HCC cell proliferation via ERK pathway in a paracrine manner,and identify periostin as a critical multifaceted extracellular regulator in the development of HCC.