The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development.
OBJECTIVE
Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer.


METHODS
We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis.


RESULTS
IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor alpha significantly reduced HKbeta-/- mouse fundic hyperplasia and ablated gp130(757F/F) mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-beta, RegIII-gamma, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130(757F/F) and HKbeta-/- tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus.


CONCLUSIONS
Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.
Howlett
Meegan
M
Gastrointestinal Research in Inflammation and Pathology (GRIP) Laboratory, Murdoch Children's Research Institute, Parkville, Australia.
Giraud
Andrew S
AS
Lescesen
Helen
H
Jackson
Cameron B
CB
Kalantzis
Anastasia
A
Van Driel
Ian R
IR
Robb
Lorraine
L
Van der Hoek
Mark
M
Ernst
Matthias
M
Minamoto
Toshinari
T
Boussioutas
Alex
A
Oshima
Hiroko
H
Oshima
Masanobu
M
Judd
Louise M
LM
D000818:Animals; D001706:Biopsy; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D005748:Gastric Fundus / Q000473:pathology / Q000502:physiology; D005753:Gastric Mucosa / Q000473:pathology / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D017370:Interleukin-11 / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D053703:Interleukin-11 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011706:Pyloric Antrum / Q000473:pathology / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology* / Q000503:physiopathology*
C508611:IL11 protein, human; C508429:Il11ra1 protein, mouse; C494200:Il6st protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D051057:Proto-Oncogene Proteins c-akt; D017506:H(+)-K(+)-Exchanging ATPase