Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation
Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation
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DOI：
10.1093/carcin/bgn141
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发表时间：
2008-07-01
期刊：
影响因子：
4.7
通讯作者：
Yang, Wancai
中科院分区：
文献类型：
--
作者：
Bi, Xiuli;Tong, Chang;Yang, Wancai
核心蛋白聚糖是富含亮氨酸的小分子蛋白聚糖基因家族的成员，在抑制癌细胞生长和转移中起重要作用。为了阐明核心蛋白聚糖在肠癌发生中的重要性，采用核心蛋白聚糖缺陷（Dcn（-/-））小鼠模型。我们发现，核心蛋白聚糖的靶向失活足以导致肠道肿瘤形成，30%的Dcn（-/-）小鼠在没有其他化学或遗传起始的情况下发生肠道肿瘤。此外，高风险饮食放大和加速了由核心蛋白聚糖缺乏引发的肿瘤。此外，Dcn（-/-）小鼠的肿瘤发生与肠道成熟的破坏有关，包括细胞分化减少和增殖增加，这与p21（WAF 1/cip 1），p27（kip 1），肠三叶因子和E-钙粘蛋白的下调以及β-连环蛋白信号的上调有关。此外，我们发现核心蛋白聚糖在人正常结肠粘膜的分化区域中高度表达，但在成对的结直肠癌组织中显著降低。综上所述，我们的数据表明，核心蛋白聚糖作为一种肿瘤抑制基因，在维持细胞成熟和肠道内稳态中起着重要作用。
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.