Matricellular protein periostin promotes colitis-associated colon tumorigenesis in mice

Abstract

Deletion of the Postn gene attenuated the tumorigenesis of CAC in mice. In vitro studies showed that genetic ablation of Postn regulated genes related to apoptosis, angiogenesis and cell proliferation, suggesting periostin has a pivotal role in colon cancer development. Abstract Periostin is expressed in inflamed colonic mucosa and colon cancer tissue; however, its role in the development of colitis-associated colon cancer (CAC) remains unclear. Wild-type and periostin-deficient (Postn(-/-)) mice were given a single intraperitoneal injection of azoxymethane at 12.5 mg/kg on day 0. Seven days later, 2% dextran sulfate sodium (DSS) was administered via drinking water for 5 days, followed by untreated, free water consumption for 16 days. This cycle was repeated three times. In vitro assays were performed using COLO205 and HCT116 cells. Small interfering RNA was used to inhibit Postn gene translation. Periostin expression was determined using colon samples from patients with CAC. Postn(-/-) mice exhibited lower tumor burden compared with wild-type mice. Exposure to azoxymethane/DSS resulted in extensive epithelial apoptosis in Postn(-/-) mice compared with that in wild-type mice. In addition, immunoreactivity for IB kinase, -catenin and COX2 was markedly reduced in Postn(-/-) mice. Expression of interleukin (IL)-1 and tumor necrosis factor (TNF-) significantly decreased, whereas that of IL-10 and transforming growth factor (TGF-) increased in peritoneal macrophages isolated from Postn(-/-) mice. Silencing of the Postn gene resulted in reduced cell viability, which was associated with caspase-3 activation, and this was reversed by treatment with recombinant periostin. Knockdown of Postn downregulated bcl-2, cIAP1, cFLIP-L, VEGF, Axin 2 and cyclin D1, and upregulated bak expression. Periostin expression was significantly increased in patients with CAC. Periostin aggravates CAC development, which suggests that periostin is a potential therapeutic target for the prevention of CAC in patients with inflammatory bowel disease.