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Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs.
J Clin Invest 2014; 124(12):5368-84JCI

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

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Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25347472

Citation

Degagné, Emilie, et al. "Sphingosine-1-phosphate Lyase Downregulation Promotes Colon Carcinogenesis Through STAT3-activated MicroRNAs." The Journal of Clinical Investigation, vol. 124, no. 12, 2014, pp. 5368-84.
Degagné E, Pandurangan A, Bandhuvula P, et al. Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J Clin Invest. 2014;124(12):5368-84.
Degagné, E., Pandurangan, A., Bandhuvula, P., Kumar, A., Eltanawy, A., Zhang, M., ... Saba, J. D. (2014). Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. The Journal of Clinical Investigation, 124(12), pp. 5368-84. doi:10.1172/JCI74188.
Degagné E, et al. Sphingosine-1-phosphate Lyase Downregulation Promotes Colon Carcinogenesis Through STAT3-activated MicroRNAs. J Clin Invest. 2014;124(12):5368-84. PubMed PMID: 25347472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. AU - Degagné,Emilie, AU - Pandurangan,Ashok, AU - Bandhuvula,Padmavathi, AU - Kumar,Ashok, AU - Eltanawy,Abeer, AU - Zhang,Meng, AU - Yoshinaga,Yuko, AU - Nefedov,Mikhail, AU - de Jong,Pieter J, AU - Fong,Loren G, AU - Young,Stephen G, AU - Bittman,Robert, AU - Ahmedi,Yasmin, AU - Saba,Julie D, Y1 - 2014/10/27/ PY - 2013/11/11/received PY - 2014/09/25/accepted PY - 2014/10/28/entrez PY - 2014/10/28/pubmed PY - 2015/7/15/medline SP - 5368 EP - 84 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 124 IS - 12 N2 - 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/25347472/Sphingosine_1_phosphate_lyase_downregulation_promotes_colon_carcinogenesis_through_STAT3_activated_microRNAs_ L2 - https://doi.org/10.1172/JCI74188 DB - PRIME DP - Unbound Medicine ER -