S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

Figure 4

STAT3/S1P/S1PR1/SPHK1/SPL-positive feed-forward loop promoting CAC. In a chronic inflammatory milieu, STAT3 is persistently activated through two pathways. (1) SphK1 produces S1P which when kept intracellular can activate the NFκB pathway leading to increased expression of SPHK1. (2) When S1P is exported out of the cells via the SPNS2 transporter, the binding of S1P to its S1PR1 activates STAT3. STAT3 upregulates IL-6 and S1PR1 expression as well as miR-181b1 and miR-21. miR-181b1 decreases the expression of the tumor-suppressor CYLD which results in derepression of the NFκB pathway. miR-21 decreases the expression of PTEN which is an antioncogene negatively regulating the PI3K/AKT pathway and positively p53. All these pathways are interrelated in an amplification loop, permitting the persistent STAT3 activation, which is involved in cell transformation and tumor progression. Bent arrows indicate transcriptional regulation.