Functions Of Periostin In The Hepatic Microenvironment Of Metastatic Colorectal Cancer

Colorectal cancer(CRC)is one of the most common malignancies worldwide and liver metastasis is the leading cause of death resulted from CRC.Periostin(POSTN),a matricellular protein,actively contributes to hepatic fibrosis and CRC metastasis;however,its function in the formation of fibrotic microenvironment for metastatic CRC cells is yet unclear.In this study,we observed that levels of POSTN and fibrosis markers a-SMA,Collagen ?,Collagen ? as well as TGF-?1 were significantly increased in liver metastases formed by CRC cells.When mice deficient in POSTN were used,the fibrotic microenvironment induced by CRC cells was alleviated,accompanied by less metastatic lesions.We further indicated that overexpression of POSTN by adenovirus in liver significantly increased the metastatic growth of CRC cells.What's more,we proved that fibrotic microenvironment induced by CCl4 promoted metastatic growth of CRC cells.POSTN deficient mice showed weaker liver fibrosis and liver metastases were significantly alleviated in CCl4 mice model.Mechanismly,challenging CRC cells with recombinant POSTN protein promoted CRC cells proliferation in vitro and induced TGF-?1 expression.We also found that TGF-?1 activated POSTN expression in hepatic stellate cells(HSC)partially by Smad3-driven transcriptional activation.Paracrine TGF-?1 may activate HSC into myofibroblasts that secrete POSTN,leading to the formation of fibrotic microenvironment and overgrowth of CRC cells.In conclusion,we elucidated the possible underlying mechanism that TGF-?1 and POSTN may mediate the crosstalk between CRC cells and HSC,thereby promoting the construction of liver fibrotic environment and the following metastatic colonizaiton.