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Cited 3 time in webofscience Cited 3 time in scopus
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Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation

Authors
Park, Seung BinChoi, Byung-ilLee, Beom JaeKim, Nam JooJeong, Yoon A.Joo, Moon KyungKim, Hyo JungPark, Jong JaeKim, Jae SeonNoh, Yoon-SeokLee, Hyun Joo
Issue Date
Aug-2020
Publisher
SPRINGER
Keywords
Sphk1; Colitis-associated cancer; Stat3
Citation
Digestive Diseases and Sciences, v.65, no.8, pp.2284 - 2293
Indexed
SCIE
SCOPUS
Journal Title
Digestive Diseases and Sciences
Volume
65
Number
8
Start Page
2284
End Page
2293
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/1287
DOI
10.1007/s10620-019-05971-2
ISSN
0163-2116
Abstract
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 Sphk1(Delta IEC)/Apc(Min/+) and Sphk1(IEC)/Apc(Min/+) 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 Apc(Min/+) mice. Histologic grade was more severe in Sphk1(Delta IEC)/Apc(Min/+) mice compared with Sphk1(IEC)/Apc(Min/+) 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 Apc(Min/+)-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.
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Park, Jong Jae
Guro Hospital (Department of Gastroenterology and Hepatology, Guro Hospital)
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