Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling.
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 gp130F/Fspontaneous 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 gp130F/Fmice 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 gp130F/Fmice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130F/Fmice 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 gp130F/F:Adam17ex/exmice 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.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.
Jesse J
JJ
Balic
Institute of Biochemistry, Christian-Albrechts-University, Olshausenstrasse 40, D-24098 Kiel, Germany.
Christoph
C
Garbers
Institute of Biochemistry, Christian-Albrechts-University, Olshausenstrasse 40, D-24098 Kiel, Germany.
Stefan
S
Rose-John
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.
Liang
L
Yu
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia. Electronic address: Brendan.Jenkins@hudson.org.au.
Brendan J
BJ
Jenkins
D000072197:ADAM10 Protein / Q000235:genetics / Q000276:immunology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D017370:Interleukin-11 / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C494200:Il6st protein, mouse; D017370:Interleukin-11; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
ADAM17; Gastric cancer; IL-11; STAT3; Trans-signalling; sgp130Fc