Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs
Emilie Degagné, … , Yasmin Ahmedi, Julie D. Saba
Emilie Degagné, … , Yasmin Ahmedi, Julie D. Saba
Published October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5368-5384. https://doi.org/10.1172/JCI74188.
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Research Article Oncology

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

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.

Authors

Emilie Degagné, Ashok Pandurangan, Padmavathi Bandhuvula, Ashok Kumar, Abeer Eltanawy, Meng Zhang, Yuko Yoshinaga, Mikhail Nefedov, Pieter J. de Jong, Loren G. Fong, Stephen G. Young, Robert Bittman, Yasmin Ahmedi, Julie D. Saba

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Figure 4

Loss of SPL in gut epithelium promotes cytokine production, PTEN and CYLD repression, and colon tumorigenesis in a STAT3-dependent manner.

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Loss of SPL in gut epithelium promotes cytokine production, PTEN and CYL...
KO mice were treated with AOM/DSS with or without NSC 74859 (10 mg/kg i.p.) or saline every other day on days 30 to 60. White bars represent KO plus saline, and black bars represent KO plus NSC 74859. (A) Colon inflammatory cytokines. (B) Average colon length. (C) Average tumor number per mouse. (D) miR-181b-1 expression. (E) miR-21 expression. (F) PTEN and CYLD protein expression. n = 6 per group. *P < 0.05.