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

Lee et al. 2010. Nat. Med. 16:1421-1429

Speaker：Fang-Hsin Chang (張芳馨)                          Time：15:00~16:00, May. 11 2011

Commentator：Dr. Li-Jin Hsu (徐麗君博士)              Place：Room 601

Abstract：

        Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in both tumor cells and tumor-infiltrating immune cells is important for cancer initiation, development, and progression [1]. Although interleukin-6 (IL-6)-Janus kinase (JAK) signaling is crucial for triggering STAT3 activation, the activation is generally transient. How STAT3 is persistently activated in tumor microenvironment is still unclear. In this article, the authors found that sphingosine-1-phosphate (S1P) receptor-1 (S1PR1), a G protein-coupled receptor, can be the answer [2]. The first clue is that S1PR1 expression is elevated in STAT3-positive tumor-infiltrating myeloid cells as compared with the STAT3-negative counterparts. STAT3 induces S1PR1 expression through promoter activation, and enhanced S1PR1 expression can activate STAT3, forming a positive feedback loop. The S1PR1-triggered STAT3 activation is persistent and requires JAK2 kinase. Interestingly, culture supernatants of tumor cells with S1PR1 induction and STAT3 activation also upregulate the STAT3-S1PR1 loop in myeloid cells, suggesting that the crosstalk between the two cell types results in constitutive STAT3 activation in both, where S1PR1 is critically involved. Silencing S1PR1 expression in either tumor cells or intratumoral hematopoietic cells not only inhibits STAT3 activity and its downstream target genes in tumor tissues, but also suppresses tumor growth and metastasis. Therefore, S1PR1 may be a novel therapeutic target to treat cancers and other inflammatory diseases where constitutive STAT3 activation plays important pathogenic roles.

References：

1.         Yu, H., M. Kortylewski, and D. Pardoll. (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7: 41-51.

2.         Rivera, J., R.L. Proia, and A. Olivera. (2008) The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat. Rev. Immunol. 8:753-63.