TY - JOUR
T1 - The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development
AU - Howlett, Meegan
AU - Giraud, Andrew S.
AU - Lescesen, Helen
AU - Jackson, Cameron B.
AU - Kalantzis, Anastasia
AU - Van Driel, Ian R.
AU - Robb, Lorraine
AU - Van der Hoek, Mark
AU - Ernst, Matthias
AU - Minamoto, Toshinari
AU - Boussioutas, Alex
AU - Oshima, Hiroko
AU - Oshima, Masanobu
AU - Judd, Louise M.
PY - 2009/3
Y1 - 2009/3
N2 - BACKGROUND & AIMS: 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.
AB - BACKGROUND & AIMS: 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.
KW - Animals
KW - Biopsy
KW - Cytokine Receptor gp130/genetics
KW - Disease Models, Animal
KW - Epithelial Cells/pathology
KW - Gastric Fundus/pathology
KW - Gastric Mucosa/pathology
KW - Gene Expression Regulation, Neoplastic
KW - H(+)-K(+)-Exchanging ATPase/genetics
KW - Homeostasis/physiology
KW - Humans
KW - Hyperplasia
KW - Interleukin-11/genetics
KW - Interleukin-11 Receptor alpha Subunit/metabolism
KW - Interleukin-6/pharmacology
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Oligonucleotide Array Sequence Analysis
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Pyloric Antrum/pathology
KW - STAT3 Transcription Factor/metabolism
KW - Stomach Neoplasms/pathology
UR - https://www.scopus.com/pages/publications/60449103529
U2 - 10.1053/j.gastro.2008.12.003
DO - 10.1053/j.gastro.2008.12.003
M3 - Article
C2 - 19121317
SN - 0016-5085
VL - 136
SP - 967
EP - 977
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -
