Good guys and bad guys

Increasing evidence supports a link between diet, inflammation, and colon cancer. In murine models, dietary supplementation with the sphingolipid sphingosine is protective against colon cancer; however, the phosphorylated form of sphingosine, sphingosine-1-phosphate (S1P), promotes tumorigenic transformation. S1P lyase (SPL), which degrades S1P, is highly expressed in healthy enterocytes but reduced in colon cancer, suggesting that sphingolipid metabolism influences colon cancer development. Emilie Degagné and colleagues at the Children’s Hospital Oakland Research Institute evaluated the contribution of SPL in colitis-associated cancer (CAC). Compared to control animals, mice lacking SPL in the intestinal epithelium were extremely susceptible to CAC, as evidenced by increased tumor formation and colon shortening in response to chemically induced colitis. S1P, STAT3 activation, STAT3-induced microRNAs, and inflammatory cytokines were all increased SPL-deficient mice, and STAT3 inhibition ameliorated CAC severity in these animals. In fibroblasts, loss of SPL enhanced extracellular transport of S1P, resulting in S1P receptor activation, induction of STAT3-dependent microRNAs, and silencing of tumor suppressor CYLD. Importantly, both S1P levels and STAT3 signaling were enhanced in biopsies from IBD patients.  In mice, administration of sphingadienes, plant-type sphingolipids that cannot be metabolized to S1P, increased SPL production, thereby reducing S1P, STAT3 signaling, and tumorigenesis in response to chemically induced colitis. The results from this study reveal that dietary sphingolipids differentially influence intestinal carcinogenesis and suggest that sphingadienes have potential as protective agents against colon cancer. The accompanying image shows enhanced proliferation (Ki-67 staining) in colon sections from mice lacking SPL in the intestine (left) compared to control animals (right) in respsone to chemically induced colitis.

Published October 27, 2014, by Corinne Williams

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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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