Cytokine signalling via gp130 in gastric cancer.
Cytokine signalling pathways that depend on gp130 are dysregulated in several epithelial cancers including gastric cancer. It has been established that blockade of SHP2 activation of MAPK signalling results in hyperactivation of STAT3 resulting in increased cell proliferation, angiogenesis, inflammation and inhibition of both immunocyte and epithelial cell apoptosis. Additionally, key genes regulated downstream of gp130 via MAPK activation such as the stomach-specific tumor suppressor gene tff1 are suppressed, contributing to the oncogenic outcome. The main cytokine driver of gp130 signalling in the stomach is IL-11, with IL-6 having little activity in the antral stomach in which most pathology initiates. IL-11 is up-regulated in both mouse and human gastric cancer and in pre-neoplastic mucosa. A characteristic gene signature specifically associated with IL-11 drive has been observed, although the prognostic value of the signature has not yet been assessed. Infection of human or mouse stomach with Helicobacter pylori, especially that expressing the CagA cytotoxin, produces constitutive MAPK activation, but also activated STAT3 and increases IL-11 expression. The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics.
Howlett
M
M
Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, 3050, Australia.
Menheniott
T R
TR
Judd
L M
LM
Giraud
A S
AS
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000188:drug therapy / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D017370:Interleukin-11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D010455:Peptides / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C508611:IL11 protein, human; C508600:IL6 protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D015850:Interleukin-6; D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C051838:TFF1 protein, human; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C080866:cagA protein, Helicobacter pylori; D050822:Cytokine Receptor gp130; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse