Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs
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
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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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 7

Oral SD induces SPL expression, reduces colon S1P levels, prevents STAT3 activation, and reduces cytokines and CAC.

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Oral SD induces SPL expression, reduces colon S1P levels, prevents STAT3...
(A) Colon S1P levels in WT mice treated with 25 mg/kg SD (n = 4) or vehicle (n = 8) for 1 week. (B) DAI of SD-treated mice compared with vehicle-treated mice. (C) Percentage of weight loss in SD-treated and vehicle-treated mice. (D) SPL expression in SD-treated DLD1 cells for 24 hours. (E) SPL, phosphorylated STAT3 (STAT3-P), and total STAT3 (STAT3-T) expression in WT mice treated with AOM/DSS plus 25 mg/kg SD or vehicle. Blots shown are from different gels. (F) Colon inflammatory cytokines in vehicle-treated (white bars) and SD-treated (black bars) mice. (G) Average tumor number per mouse in vehicle, SD-treated, or sphingosine-treated (25 mg/kg) mice. (H) IF of activated STAT3 phosphorylated on Tyr705 (STAT3-P, green) in colon tissues of SD-treated and vehicle-treated mice. Nuclei were counterstained with DAPI. Scale bar: 50 μm. (I) PTEN and CYLD protein expression in colons of SD-treated and vehicle-treated mice. *P < 0.05.