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.
The c-Jun NH 2 -terminal kinase (JNK) signal transduction pathway plays important roles in cellular processes and stress. However, the role of JNK1 in intestinal homeostasis and tumorigenesis is unknown. Therefore, we used a JNK1 knockout mouse model to characterize intestinal cell maturation and tumorigenesis. In addition, colon cancer cell lines were used to validate the role of JNK1 and to elucidate the underlying molecular mechanisms in vitro. To our surprise, we found that mice with targeted inactivation of JNK1 spontaneously developed intestinal tumors. The normal mucosa in JNK1-deficient mice showed decreased cell differentiation and increased cell proliferation. This tumorigenesis was closely linked to the down-regulation of p21 WAF1/cip1 , a cyclin-dependent kinase inhibitor, in intestinal epithelial cells. Immunohistochemical staining showed that JNK1 was highly expressed in the differentiation compartment of the intestinal mucosa and that the expression of JNK1 was significantly decreased in both human colonic and mouse intestinal tumors. In the colon cancer cell lines, JNK1 expression was up-regulated during spontaneous differentiation, corresponding to the up-regulation of p21 WAF1/cip1 . Moreover, butyrateinduced p21 expression was linked to phosphorylation of JNK1. Reduced JNK1 expression by small interfering RNA suppressed butyrate-induced apoptosis. We concluded that JNK1 plays a critical role in the regulation of homeostasis and in the suppression of tumor formation in the intestine, which was linked to the altered expression of p21 WAF1/cip1 .
Our previous studies demonstrated that sulindac, a non-steroidal anti-inflammatory drug, suppressed intestinal tumor formation in mouse, which is linked to the induction of wild-type p53-activated fragment 1 (p21WAF1, or p21). Here we showed that sulindac also required c-Jun N-terminal Kinase 1 (JNK1) to inhibit cell proliferation and induce apoptosis in vitro and in vivo. First, sulindac inhibited cell proliferation and induced apoptosis in colon cancer cell lines HCT116 with wild-type p21 or null p21, which were p21-dependent and were also associated with the induction of p21 and phosphorylation of JNK1. Second, sulindac increased apoptosis in JNK1(+/+) and JNK1(-/-) mouse embryonic fibroblast (MEF) cells, but, the increase of apoptosis in JNK1(+/+) cells was more than that in JNK1(-/-) cells. More interestingly, sulindac significantly inhibited cell proliferation in JNK1(+/+) cells, but the inhibition in JNK1(-/-) cells markedly decreased. Further studies indicated that JNK1 was dramatically induced by sulindac in the JNK1(+/+) cells which correlated with the induction of p21. However, the induction of p21 in JNK1(-/-) cells was less than that in JNK1(+/+) cells. Finally, we determined the expression of JNK1 in the intestinal mucosa of Apc(+/-), p21(+/+) mice, and found that sulindac significantly induced JNK1 phosphorylation, corresponding to the induction of p21, both in mRNA and protein levels. Our data indicates that sulindac-mediated proliferation inhibition and apoptosis induction were not only p21-dependent, but also required JNK1.
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