| First Author | Balic JJ | Year | 2017 |
| Journal | Cytokine | Volume | 92 |
| Pages | 118-123 | PubMed ID | 28160627 |
| Mgi Jnum | J:320874 | Mgi Id | MGI:6880981 |
| Doi | 10.1016/j.cyto.2017.01.015 | Citation | Balic JJ, et al. (2017) Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling. Cytokine 92:118-123 |
| abstractText | Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130(F/F) spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis. sIL-11R protein was detectable in gastric tissue from GC patients, and sIL-11R levels were elevated in tumours of gp130(F/F) mice compared to matched non-tumours. Among candidate proteases associated with the generation of sIL-11R, ADAM10 and the related metalloprotease ADAM17 were significantly upregulated in tumours of both gp130(F/F) mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130(F/F) mice upon the transgenic over-expression of the trans-signalling antagonist, sgp130Fc, failed to suppress gastric inflammation and associated tumour growth, and also had no effect on reducing hyper-activated STAT3 levels. Furthermore, a non-essential role for ADAM17 in IL-11-driven gastric tumourigenesis was supported by the observation that the tumour burden was unaffected in gp130(F/F):Adam17(ex/ex) mice in which ADAM17 expression levels have been substantially reduced. Collectively, these findings suggest that classic signalling rather than trans-signalling is the mode by which IL-11 promotes gastric tumourigenesis. |
