Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9.
Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9.
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DOI：
10.18632/oncotarget.5440
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Mizoguchi E
中科院分区：
文献类型：
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作者：
Low D;Subramaniam R;Lin L;Aomatsu T;Mizoguchi A;Ng A;DeGruttola AK;Lee CG;Elias JA;Andoh A;Mino-Kenudson M;Mizoguchi E
许多宿主因子在炎症性肠病（IBD）的发展过程中可诱导表达，每种因子都具有其独特的性质，例如免疫激活、细菌清除和组织修复/重塑。这些因素的失调/失衡可能具有致病作用，可导致结肠炎相关癌症（CAC）。先前的报道表明，IBD患者诱导表达结肠几丁质酶3样1（CHI 3L 1），其在CAC发展期间进一步上调。然而，很少有人知道CHI 3L 1在体内的直接致病参与。在这里，我们证明，CHI 3L 1（又名Brp 39）敲除（KO）小鼠与氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）治疗发展严重的结肠炎，但较低的发病率CAC相比，野生型（WT）小鼠。最高的CHI 3L 1表达被发现在结肠炎的慢性期，而不是急性期，是必不可少的，以促进肠上皮细胞（IEC）在体内增殖。这种CHI 3L 1介导的细胞增殖/存活涉及促凋亡S100 A9蛋白的部分下调，所述促凋亡S100 A9蛋白通过与S100 A9受体（晚期糖基化终产物受体）结合而在结肠炎急性期高度表达。这种相互作用破坏了早期免疫激活过程中S100 A9相关表达的正反馈环，创造了CHI 3L 1hi S100 A9低结肠环境，特别是在结肠炎的后期，这促进了正常IEC和肿瘤细胞的细胞增殖/存活。
Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1hi S100A9low colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells.