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

Nat Med. 2010 Dec;16(12):1421-8. doi: 10.1038/nm.2250. Epub 2010 Nov 21.


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.

Publication types

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

MeSH terms

  • Animals
  • Chromatin Immunoprecipitation
  • DNA Primers / genetics
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Feedback, Physiological / physiology
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Neoplasms / metabolism*
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*


  • DNA Primers
  • Interleukin-6
  • Receptors, Lysosphingolipid
  • STAT3 Transcription Factor
  • Stat3 protein, mouse