Abstract 1448: Interaction between decorin and E-cadherin/beta-catenin signaling attenuates colorectal cancer growth and metastasis in vitro and in decorin knockout mice

Abstract

Abstract Decorin is a small leucine-rich proteoglycan. Previous studies have demonstrated that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene caused intestinal tumor formation in mice, which was linked to a downregulation of p21, p27kip1 and E-cadherin and an upregulation of β-catenin signaling. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using manipulated colorectal cancer cells and decorin knockout mouse model (Dcn-/- mice), we found that increasing decorin expression in colorectal cancer cells delayed cancer cell growth, accelerated apoptosis, and importantly, attenuated cancer cell migration, invasion and wound healing. Mechanistic study revealed that the attenuation of cancer cell malignancy was resulted from the interaction between decorin and E-cadherin, a protein that regulates cell-cell adhesion, epithelial-mesenchymal transition and metastasis. First, overexpression of decorin led to upregulation of E-cadherin through increasing of E-cadherin protein stability, while E-cadherin mRNA and promoter activity were not affected; Second, co-immunoprecipitation assay showed that decorin physically bound E-cadherin. In addition, the upregulation of E-cadherin was associated with reduction of β-catenin, c-myc and CDK4. cDNA microarray analysis also showed that the levels of two proteins involved in metastasis were altered, the extracellular proteinase inhibitor (EXPI) was significantly downregulated and Claudin 2 was upregulated in intestinal epithelial cells of the Dcn-/- mice. Moreover, loss of decorin accelerated murine cancer cell MC38 growth and invasion in the flank of Dcn-/- mice. Taken together, our results provide direct evidence that decorin-mediated inhibition of colorectal cancer formation and metastasis is through the interaction between decorin and E-cadherin/beta-catenin signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1448. doi:10.1158/1538-7445.AM2011-1448