BACKGROUND AND AIMS Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. METHODS We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). RESULTS CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation. CONCLUSIONS Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.

中文翻译：

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Sphk1的肠上皮删除通过抑制上皮STAT3激活来防止结肠炎相关的癌症发展。

背景与目的结肠炎相关癌（CAC）是炎性肠病患者最严重的并发症之一。鞘氨醇激酶1（Sphk1）是鞘脂途径中的关键酶，具有致癌基因潜力，可诱导肿瘤的发生和发展。这项工作的目的是表征上皮Sphk1在小鼠结肠炎和CAC模型中的作用。方法我们通过在肠上皮细胞（IEC）中条件性删除Sphk1，研究了Sphk1在CAC中的作用。结果通过施用2％的葡聚糖硫酸钠（DSS）7天，在Sphk1ΔIEC/ ApcMin / +和Sphk1IEC / ApcMin / +小鼠中都诱导了CAC。Sphk1的基因删除显着减少了ApcMin / +小鼠的肿瘤数量和大小。与Sphk1IEC / ApcMin / +小鼠相比，Sphk1ΔIEC/ ApcMin / +小鼠的组织学等级更为严重（浸润性癌，分别为71％和13％，p <0.05）。Sphk1的缺失降低了肿瘤细胞中的粘膜增殖并抑制了STAT3的活化以及cyclin D1和cMyc的基因表达。在HCT 116细胞中使用CRISPR-Cas9有条件地删除Sphk1可抑制白介素（IL）-6介导的STAT3激活。结论Sphk1的上皮条件性缺失可通过抑制STAT3激活及其靶信号通路来抑制ApcMin / +-DSS模型小鼠的CAC。在HCT 116细胞中使用CRISPR-Cas9有条件地删除Sphk1可抑制白介素（IL）-6介导的STAT3激活。结论Sphk1的上皮条件性缺失可通过抑制STAT3激活及其靶信号通路来抑制ApcMin / +-DSS模型小鼠的CAC。在HCT 116细胞中使用CRISPR-Cas9有条件地删除Sphk1可抑制白介素（IL）-6介导的STAT3激活。结论Sphk1的上皮条件性缺失可通过抑制STAT3激活及其靶信号通路来抑制ApcMin / +-DSS模型小鼠的CAC。