Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation

Seung Bin Park, Byung il Choi, Beom Jae Lee, Nam Joo Kim, Yoon A. Jeong, Moon Kyung Joo, Hyo Jung Kim, Jong Jae Park, Jae Seon Kim, Yoon Seok Noh, Hyun Joo Lee

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)2284-2293
Number of pages10
JournalDigestive Diseases and Sciences
Volume65
Issue number8
DOIs
Publication statusPublished - 2020 Aug 1

Keywords

  • Colitis-associated cancer
  • Sphk1
  • Stat3

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

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  • Cite this

    Park, S. B., Choi, B. I., Lee, B. J., Kim, N. J., Jeong, Y. A., Joo, M. K., Kim, H. J., Park, J. J., Kim, J. S., Noh, Y. S., & Lee, H. J. (2020). Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation. Digestive Diseases and Sciences, 65(8), 2284-2293. https://doi.org/10.1007/s10620-019-05971-2