Abstract
Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin in human colorectal cancer cells, we found that E-cadherin, a protein that regulates cell-cell adhesion, epithelial-mesenchymal transition and metastasis, was almost completely lost in Dcn(-/-) mouse intestine, and loss of decorin and E-cadherin accelerated colon cancer cell growth and invasion in Dcn(-/-) mice. However, increasing decorin expression in colorectal cancer cells attenuated cancer cell malignancy, including inhibition of cancer cell proliferation, promotion of apoptosis and importantly, attenuation of cancer cell migration. All these changes were linked to the regulation of E-cadherin by decorin. Moreover, overexpression of decorin upregulated E-cadherin through increasing of E-cadherin protein stability as E-cadherin messenger RNA and promoter activity were not affected. Co-immunoprecipitation assay showed a physical binding between decorin and E-cadherin proteins. Taken together, our results provide direct evidence that decorin-mediated inhibition of colorectal cancer growth and migration are through the interaction with and stabilization of E-cadherin.
Highlights
Decorin is a member of the small leucine-rich proteoglycan family that is primarily synthesized by fibroblasts and myofibroblasts and regulates collagen fibrillogenesis
Knockdown decorin expression led to reduced expression of E-cadherin in vitro To validate decorin-caused reduction of E-cadherin in vitro, we transfected the HEK293 cells with a small interfering RNA (siRNA) targeting decorin to knockdown decorin expression and found that E-cadherin was reduced compared with the control (Figure 1B)
Loss of decorin accelerated cancer cell growth and invasion in mice To determine whether decorin-mediated loss of E-cadherin influences tumor growth and invasion in mice, we inoculated murine colon carcinoma MC38 cells (C57BL/6 background) (2.5 Â 106 cells per mice) subcutaneously in DcnÀ/À and þ/þ mice (C57BL/6 background) for 14 days
Summary
Decorin is a member of the small leucine-rich proteoglycan family that is primarily synthesized by fibroblasts and myofibroblasts and regulates collagen fibrillogenesis It is involved in a number of physiological and pathological processes including the control of osteogenic stem cells, muscular development, wound healing and cancer [1,2]. Increasing decorin expression in colon, breast and squamous cancer cell lines suppresses their growth and progression These effects are associated with the induction of p21 [4,5,6], interaction with transforming growth factor b [5,7,8] and epithelial growth factor receptor (EGFR) [9,10,11]. Loss of decorin accelerates malignant lymphomas in p53 mutant mice, Abbreviations: EGFR, epithelial growth factor receptor; mRNA, messenger RNA; siRNA, small interfering RNA
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