Other
12 Authors
- Kujawski M,
- Liu Y,
- Yu H,
- Herrmann A,
- Kortylewski M,
- Yang C,
- Jove R,
- Somlo G,
- Deng J,
- Horne D,
- Forman S,
- Lee H
| First Author | Lee H | Year | 2010 |
| Journal | Nat Med | Volume | 16 |
| Issue | 12 | Pages | 1421-8 |
| PubMed ID | 21102457 | Mgi Jnum | J:167520 |
| Mgi Id | MGI:4868503 | Doi | 10.1038/nm.2250 |
| Citation | Lee H, et al. (2010) STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med 16(12):1421-8 |
| abstractText | 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. |
