Figure 6.

Schematic of the IL-6/STAT3/HIF-1α autocrine signaling loop that mediates the interaction between IL-6 and HIF-1α in the acquisition of EMT and invasion under hypoxic conditions. Solid lines indicate a direct action and dotted lines show an indirect action. IL-6 in the tumor microenvironment binds to its receptor and thereupon triggers the phosphorylation and nuclear localization of STAT3 by Janus kinase 2. Activated STAT3 dimers bound to specific sites in target gene promoters inducing transcription of HIF-1α. In turn, HIF-1α facilitates IL-6 production indirectly through proinflammatory mediators, such as NF-κB, COX-2, or TLR4. More IL-6 is secreted out of EOC cells, further reinforcing this loop. Among these components of the loop, STAT3 and HIF-1α have been shown to regulate the expression of EMT markers as well as EMT-related transcription factors, leading to the invasion and metastasis of EOC cells.