Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation

Abstract

Summary: Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer. : Ma et al. demonstrate that fibroblast-derived periostin promotes colorectal tumorigenesis by enhancing YAP/TAZ nuclear localization and IL-6 expression in tumor cells. Conversely, IL-6 promotes periostin expression in fibroblasts via STAT3 signaling. This work identifies crosstalk between stromal cells and tumor cells via periostin and IL-6 during colorectal tumorigenesis. Keywords: periostin, extracellular matrix, colorectal cancer, colitis-associated cancer, cancer-associated fibroblast, cell proliferation, YAP, IL-6, tumorigenesis, stromal cell