Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation

Abstract

Decorin is a member of the small leucine-rich proteoglycan gene family and plays an important role in suppressing cancer cell growth and metastasis. To elucidate the importance of decorin in intestinal carcinogenesis, a decorin-deficient (Dcn(-/-)) mouse model was employed. We found that targeted inactivation of decorin was sufficient to cause intestinal tumor formation with 30% of the Dcn(-/-) mice developing intestinal tumors with no other chemical or genetic initiation. Moreover, a high-risk diet amplified and accelerated the tumors initiated by decorin deficiency. Further, tumorigenesis in Dcn(-/-) mice was associated with disruption of intestinal maturation, including decreased cell differentiation and increased proliferation, which were linked to the downregulation of p21(WAF1/cip1), p27(kip1), intestinal trefoil factor and E-cadherin and to the upregulation of beta-catenin signaling. In addition, we found that decorin was highly expressed in the differentiated area of human normal colonic mucosa, but was dramatically reduced in paired colorectal cancer tissues. Taken together, our data demonstrate that decorin acts as a tumor suppressor gene and plays an important role in the maintenance of cell maturation and therefore homeostasis in the intestinal tract.

Methylated +58CpG site decreases DCN mRNA expression and enhances TGF-β/Smad signaling in NSCLC cells with high metastatic potential

“…Compelling evidence has shown that DCN contributes to inhibition of tumor growth and metastasis (13,(15)(16)(17)(18)(19)34). Goldoni et al reported that DCN can display an anti-metastatic role in breast cancer (16).…”

“…Goldoni et al reported that DCN can display an anti-metastatic role in breast cancer (16). Bi et al demonstrated that DCN may act as a tumor suppressor gene (15) and mediate inhibition of colorectal cancer growth and migration (13). Among soft tissue tumor patients with recurrent or metastatic lesions, lower levels of DCN were expressed in secondary lesions than those in primary lesions (17).…”

“…DCN-mediated inhibition of colorectal cancer migration is associated with E-cadherin (13,(15)(16)(17)(18)(19)34). Here we examined expression of E-cadherin in 95D expressing low DCN and 95C expressing high DCN, and found that E-cadherin expression was significantly lower in 95D cells (0.25±0.05) than 95C cells (0.73±0.07) (P=0.016) (Fig.…”

“…Accumulative evidence shows that DCN plays an inhibitory role in tumor growth and metastasis (15)(16)(17)(18)(19). This role can be played through DCN specifically binding to TGF-β and partially blocking the TGF-β signaling pathway, leading to growth suppression of distant tumors including lung cancer (20)(21)(22).…”

A Central Role for Decorin during Vertebrate Convergent Extension

“…In line with this hypothesis, a recent study utilizing decorin-null animals, which were backcrossed into a different genetic background, has shown that the lack of decorin favors spontaneous occurrence of intestinal tumors in ϳ30% of the cases, and this tumor burden and frequency were exacerbated by subjecting the mutant mice to a high risk diet (35).…”