Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs

Degagne, Emilie, Pandurangan, Ashok, Bandhuvula, Padmavathi, Kumar, Ashok, Eltanawy, Abeer, Zhang, Meng, Yoshinaga, Yuko, Nefedov, Mikhail, de Jong, Pieter J., Fong, Loren G., Young, Stephen G., Bittman, Robert, Ahmedi, Yasmin and Saba, Julie D. (2014) Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. Journal of Clinical Investigation, 124 12: 5368-5384. doi:10.1172/JCI74188

Author Degagne, Emilie
Pandurangan, Ashok
Bandhuvula, Padmavathi
Kumar, Ashok
Eltanawy, Abeer
Zhang, Meng
Yoshinaga, Yuko
Nefedov, Mikhail
de Jong, Pieter J.
Fong, Loren G.
Young, Stephen G.
Bittman, Robert
Ahmedi, Yasmin
Saba, Julie D.
Title Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 1558-8238
Publication date 2014-12-01
Year available 2014
Sub-type Article (original research)
DOI 10.1172/JCI74188
Open Access Status DOI
Volume 124
Issue 12
Start page 5368
End page 5384
Total pages 17
Place of publication Ann Arbor, MI United States
Publisher American Society for Clinical Investigation
Collection year 2014
Language eng
Formatted abstract
Growing evidence supports a link between inflammation and cancer; however, mediators of the transition between inflammation and carcinogenesis remain incompletely understood. Sphingosine-1-phosphate (S1P) lyase (SPL) irreversibly degrades the bioactive sphingolipid S1P and is highly expressed in enterocytes but downregulated in colon cancer. Here, we investigated the role of SPL in colitis-associated cancer (CAC). We generated mice with intestinal epithelium-specific Sgpl1 deletion and chemically induced colitis and tumor formation in these animals. Compared with control animals, mice lacking intestinal SPL exhibited greater disease activity, colon shortening, cytokine levels, S1P accumulation, tumors, STAT3 activation, STAT3-activated microRNAs (miRNAs), and suppression of miR-targeted anti-oncogene products. This phenotype was attenuated by STAT3 inhibition. In fibroblasts, silencing SPL promoted tumorigenic transformation through a pathway involving extracellular transport of S1P through S1P transporter spinster homolog 2 (SPNS2), S1P receptor activation, JAK2/STAT3-dependent miR-181b-1 induction, and silencing of miR-181b-1 target cylindromatosis (CYLD). Colon biopsies from patients with inflammatory bowel disease revealed enhanced S1P and STAT3 signaling. In mice with chemical-induced CAC, oral administration of plant-type sphingolipids called sphingadienes increased colonic SPL levels and reduced S1P levels, STAT3 signaling, cytokine levels, and tumorigenesis, indicating that SPL prevents transformation and carcinogenesis. Together, our results suggest that dietary sphingolipids can augment or prevent colon cancer, depending upon whether they are metabolized to S1P or promote S1P metabolism through the actions of SPL.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
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