| Abnormal expression of the extracellular matrix protein is closely related to tumor progression.The secreted protein periostin,which contains Fas1 domains,belongs to extracellular matrix proteins and highly expresses in the damaged tissue sites,inflammatory disorders and tumor tissues.Current studies have revealed that periostin can promote tissue repair and inflammatory diseases and tumor development.Our previous work demonstrated that periostin promotes colorectal cancer liver metastasis via activation of PI3K/Akt pathway to enhance angiogenesis and tumor cell survival.However,it remains largely unknown whether and how periostin is involved in colorectal tumorigenesis,especially in the development of colitis-associated colorectal cancer(CAC).Using AOM/DSS mouse model of CAC,we found that Postn-/-mice have significantly reduced colitis disease severity and the degree of tissue damage compared to wild-type mice.Absence of periostin largely decreases the number of immune cells infiltrated in the distal colon tissues.Our study further revealed that periostin-deficiency mice exhibit less sensitivity to AOM/DSS-induced colorectal tumor formation and less proliferative tumor cells.With similar results observed in AOM/DSS mouse model,absence of periostin greatly reduces the ability of colorectal tumor formation in ApcMin/+ mice.Stromal cell-secreted periostin can enhance tumor cell proliferation through the integrin-FAK-Src axis mediated YAP/TAZ activation.Knock down of YAP/TAZ in tumor cells or especially interdicts the upstream kinases by specific inhibitors can significantly reveres the tumor cell proliferation induced by periostin.Activation of YAP upregulates IL-6 expression,which in turn stimulates myofibroblast cell activation and periostin expression dependent on STAT3 signaling activation.Taken together,our findings revealed that under the pathological conditions of inflammation and/or tumor,the elevation of IL-6 can stimate colon myofibroblast activation and periostin expression;subsequently,stromal fibroblast-derived periostin induces YAP/TAZ activation and IL-6 expression through integrin-FAK-Src axis.Therefore,our study provides strong evidence to support the notion that the periostin-IL-6 loop contributes to regulating the interaction between tumor cells and fibroblasts during colorectal tumorigenesis.Targeting periostin-and IL-6-mediated tumor-stroma interaction may be an attractive therapeutic strategy for human colorectal tumors. |
