The Functions Of Periostin Knockout Or Overexpression On Liver Metastasis Of Colorectal Cancer In Mice

As an extracellular matrix protein,periostin has been reported to be highly expressed in both orthotopic colorectal tumors and liver metastases during the progression of colorectal cancer,suggesting that periostin may be involved in the progression and metastasis of colorectal cancer.Periostin has also been shown to regulate the process of liver fibrosis,which is associated with liver metastasis from a variety of cancers.Our previous studies have shown that knockout of periostin inhibits liver metastasis from colorectal cancer,and overexpression of periostin in the liver promotes liver metastasis from colorectal cancer,but the specific role of periostin in this process for colorectal cancer cells remains unclear.In this study,we used two kinds of background C57BL/6 and BALB/C mice and found that periostin knockout can reduce the proliferation of colorectal cancer cell in liver metastases,and the mice liver weight ratio is reduced.We further found that periostin-knockout mice with liver metastasis of colorectal cancer survive longer than the wild type mice with liver metastasis of colorectal cancer.Overexpression of Periostin in mouse liver can promote the proliferation of colorectal cancer cells in liver metastases by generating a fibrotic microenvironment with upregulated collagen deposition,and TGF-?expression.Meanwhile,we found that overexpression of periostin also promotes the formation of inflammatory microenvironment in liver metastases.Mechanistically,periostin can activate FAK and ERK pathways to regulate the expression of TGF-?,while TGF-? regulates periostin expression through Smad-dependent pathway.In the clinical samples of patients with colorectal cancer,we found that the tumor microenvironment of liver metastasis is similar to the primary colorectal cancer samples,both of which form fibrotic microenvironment with activated hepatic stellate cells,collagen deposition,and phosphorylated Smad3 in activated hepatic stellate cells.These results from periostin knockout mice and periostin-overexpression mice suggest that periostin has a significant effect on liver metastasis of colorectal cancer cells.This study will help us to further elucidate the functions and mechanisms of periostin in liver metastasis of colorectal cancer.