Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis.
Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis.
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DOI：
10.18632/oncotarget.26335
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发表时间：
2018-11-23
期刊：
影响因子：
--
通讯作者：
Parry, Lee
中科院分区：
文献类型：
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作者：
Greenow, Kirsty R;Zverev, Matthew;Parry, Lee
白细胞衍生趋化素2(Lect2)是一种趋化因子样的趋化因子，已被认为是Wnt信号通路的下游靶点。虽然Lect2的主要功能被认为是调节炎症过程，但它最近被认为是Wnt途径的潜在抑制物。在大约80%的结直肠癌(CRC)中发现Wnt途径的失控，通常是由于负调控因子APC的缺失。在这里，我们使用ApcMin/+Lect2-/-小鼠模型来表征Lect2在Wnt驱动的肠道肿瘤发生中的作用。采用组织病理学、免疫组织化学、聚合酶链式反应和流式细胞仪分析等方法鉴定Lect2在肠道中的作用。随着严重程度的增加，ApcMin/+Lect2-/-小鼠的平均存活率降低，小肠腺瘤数量显著增加。对Lect2缺失的分析表明，它对肠道中的Wnt途径没有影响，但在循环炎症标志物、CD4+T细胞和T细胞谱系特异性因子方面观察到显著差异。综上所述，在小鼠肠道中，Lect2的缺失促进了Wnt驱动的结直肠癌的发生和发展。这种保护是独立于Wnt信号通路进行的，并与Wnt驱动的肿瘤发生过程中炎症环境的改变有关。
Leukocyte cell-derived chemotaxin 2 (Lect2) is a chemokine-like chemotactic factor that has been identified as a downstream target of the Wnt signalling pathway. Whilst the primary function of Lect2 is thought to be in modulating the inflammatory process, it has recently been implicated as a potential inhibitor of the Wnt pathway. Deregulation of the Wnt pathway, often due to loss of the negative regulator APC, is found in ~80% of colorectal cancer (CRC). Here we have used the ApcMin/+Lect2-/- mouse model to characterise the role of Lect2 in Wnt-driven intestinal tumourigenesis. Histopathological, immunohistochemical, PCR and flow cytometry analysis were employed to identify the role of Lect2 in the intestine. The ApcMin/+Lect2-/- mice had a reduced mean survival and a significantly increased number of adenomas in the small intestine with increased severity. Analysis of Lect2 loss indicated it had no effect on the Wnt pathway in the intestine but significant differences were observed in circulating inflammatory markers, CD4+ T cells, and T cell lineage-specification factors. In summary, in the murine intestine loss of Lect2 promotes the initiation and progression of Wnt-driven colorectal cancer. This protection is performed independently of the Wnt signalling pathway and is associated with an altered inflammatory environment during Wnt-driven tumorigenesis.