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Cited by 395Cytokine Signaling Pathways and InteractionsSphingolipid Metabolism and SignalingCancer, Lipids, and Metabolism

STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors

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Lee, Heehyoung, Deng, Jiehui, Kujawski, Maciej, Yang, Chunmei, Liu, Yong, Herrmann, Andreas, Kortylewski, Marcin, Horne, David +4 more·2010·Nature Medicine
DOI 10.1038/nm.2250PMC PMC3088498
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Abstract

Interleukin-6 (IL-6)-Janus kinase (JAK) signaling is viewed as crucial for persistent signal transducer and activator of transcription-3 (STAT3) activation in cancer. However, IL-6-induced STAT3 activation is normally transient. Here we identify a key mechanism for persistent STAT3 activation in tumor cells and the tumor microenvironment. We show that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in STAT3-positive tumors. STAT3 is a transcription factor for the S1pr1 gene. Reciprocally, enhanced S1pr1 expression activates STAT3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis in a STAT3-dependent manner. Silencing S1pr1 in tumor cells or immune cells inhibits tumor STAT3 activity, tumor growth and metastasis. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient STAT3 activation by IL-6. S1PR1 activates STAT3 in part by upregulating JAK2 tyrosine kinase activity. We show that STAT3-induced S1PR1 expression, as well as the S1P-S1PR1 pathway reciprocal regulation of STAT3 activity, is a major positive feedback loop for persistent STAT3 activation in cancer cells and the tumor microenvironment and for malignant progression.

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  • S1P activates STAT3 through its G protein-coupled receptor, S1P receptor-1.

    “Lysophospholipid sphingosine-1-phosphate (S1P), a lipid metabolite, activates STAT3 through its G protein-coupled receptor, S1P receptor-1 (309).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [309]

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References 41 · Cited by 395

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Authors
Lee, H., Deng, J., Kujawski, M., Yang, C., Liu, Y., Herrmann, A., Kortylewski, M., Horne, D., Somlo, G., Forman, S., Jove, R., & Yu, H.
Affiliations
City Of Hope National Medical Center (US)
Corresponding author
Yu, Hua
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-11-21
Volume
16
Issue
12
Pages
1421-1428
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2250
PMC
PMC3088498
OpenAlex
W1982334431
Cited by
395
References
41
Citations by year
2026: 12 · 2025: 12 · 2024: 14 · 2023: 16 · 2022: 18 · 2021: 30 · 2020: 37 · 2019: 25 · 2018: 31 · 2017: 24 · 2016: 27 · 2015: 24 · 2014: 38 · 2013: 38 · 2012: 33
FWCI
13.46
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (P50CA107399, R01CA115674, R01CA122976, CA33572, R01CA140692, R01CA115815, P30CA033572)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
STAT3, S1PR1, sphingosine-1-phosphate, positive feedback loop, tumor microenvironment, metastasis, tumor growth, JAK2, interleukin-6, oncogenic signaling, G protein-coupled receptors, transcriptional regulation
MeSH terms
Animals, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Neoplasms, Interleukin-6, Gene Expression Regulation, Neoplastic, DNA Primers, Mice, Knockout, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Electrophoretic Mobility Shift Assay, Feedback, Physiological, Chromatin Immunoprecipitation, Immunoprecipitation, Receptors, Lysosphingolipid, STAT3 Transcription Factor, Mice

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