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

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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Figure 1: Stat3 activity in tumors promotes S1pr1 expression.
Figure 2: Stat3 is a direct transcriptional activator of S1pr1.
Figure 3: Overexpression of S1pr1 in tumor cells promotes tumor progression and activates Stat3.
Figure 4: Elevated S1PR1 expression in tumor cells increases Stat3 activation and S1pr1 expression in tumor-infiltrating myeloid cells.
Figure 5: S1P-S1PR1–induced Stat3 activation is persistent and mediated by Jak2.
Figure 6: Targeting S1pr1 in either tumor cells or the tumor microenvironment inhibits Stat3 activity, tumor growth and metastasis.

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Acknowledgements

We thank the flow cytometry core, light microscopy core, pathology core and translational research core, as well as the animal facility, of the Beckman Research Institute at City of Hope for their superb technical assistance. We would also like to thank P. Chu for evaluating histology of breast cancer tissue sections, R.L. Proia at US National Institutes of Health for generously providing the S1pr1flox/flox mice, V. Poli (University of Turin) for Stat3−/− MEF cells, T. Ratliff (University of Iowa) for MB49 mouse bladder transitional cell carcinoma cell line, A. Raubitschek (City of Hope Medical Center) for Jurkat human T cell leukemia and Karpas 299 human T cell lymphoma cell lines and S. Priceman for critical reading of this manuscript. This work is funded by US National Institutes of Health grants R01CA115815, R01CA115674, R01CA122976 and P50CA107399. Procurement of clinical specimens used in the study was supported by grants from the National Cancer Institute CA 33572 and American Bioscience.

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H.Y. and H.L. developed the concept, designed experiments and prepared the manuscript. H.L. also carried out most of the experiments, the data organization and the statistical analyses. J.D., M. Kujawski and Y.L. performed mouse experiments. C.Y. carried out tissue microdissection and RNA preparation. M. Kortylewski performed flow cytometry. Confocal microscopy was performed by A.H. R.J. made conceptual contributions to the studies, particularly about the S1P-Src and Jak2-Stat3 relationships. G.S. and S.F. contributed to the studies for providing clinical relevance of the findings. D.H. synthesized chemical inhibitors that allowed us to perform additional confirmatory experiments.

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Correspondence to Hua Yu.

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Lee, H., Deng, J., Kujawski, M. et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med 16, 1421–1428 (2010). https://doi.org/10.1038/nm.2250

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