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
JournalDigestive Diseases and Sciences
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Sphingosine
Colitis
Neoplasms
Dextran Sulfate
Clustered Regularly Interspaced Short Palindromic Repeats
HCT116 Cells
Sphingolipids
Oncogenes
Inflammatory Bowel Diseases
Interleukin-6
Epithelial Cells
Carcinoma
Enzymes

Keywords

  • Colitis-associated cancer
  • Sphk1
  • Stat3

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

Cite this

Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation. / Park, Seung Bin; Choi, Byung il; Lee, Beom Jae; Kim, Nam Joo; Jeong, Yoon A.; Joo, Moon Kyung; Kim, Hyo Jung; Park, Jong Jae; Kim, Jae Seon; Noh, Yoon Seok; Lee, Hyun Joo.

In: Digestive Diseases and Sciences, 01.01.2019.

Research output: Contribution to journalArticle

@article{e738f2e08b134f6da0d1b6970baaa1dd,
title = "Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation",
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.",
keywords = "Colitis-associated cancer, Sphk1, Stat3",
author = "Park, {Seung Bin} and Choi, {Byung il} and Lee, {Beom Jae} and Kim, {Nam Joo} and Jeong, {Yoon A.} and Joo, {Moon Kyung} and Kim, {Hyo Jung} and Park, {Jong Jae} and Kim, {Jae Seon} and Noh, {Yoon Seok} and Lee, {Hyun Joo}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s10620-019-05971-2",
language = "English",
journal = "American Journal of Digestive Diseases",
issn = "0002-9211",
publisher = "Springer New York",

}

TY - JOUR

T1 - Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation

AU - Park, Seung Bin

AU - Choi, Byung il

AU - Lee, Beom Jae

AU - Kim, Nam Joo

AU - Jeong, Yoon A.

AU - Joo, Moon Kyung

AU - Kim, Hyo Jung

AU - Park, Jong Jae

AU - Kim, Jae Seon

AU - Noh, Yoon Seok

AU - Lee, Hyun Joo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Colitis-associated cancer

KW - Sphk1

KW - Stat3

UR - http://www.scopus.com/inward/record.url?scp=85075611255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075611255&partnerID=8YFLogxK

U2 - 10.1007/s10620-019-05971-2

DO - 10.1007/s10620-019-05971-2

M3 - Article

AN - SCOPUS:85075611255

JO - American Journal of Digestive Diseases

JF - American Journal of Digestive Diseases

SN - 0002-9211

ER -