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.
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 humangastric cancer. METHODS: We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mousegastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancerpatients. 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-/- mousefundic 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 cancerpatients. 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.
Authors: Michael Quante; Govind Bhagat; Julian A Abrams; Frederic Marache; Pamela Good; Michele D Lee; Yoomi Lee; Richard Friedman; Samuel Asfaha; Zinaida Dubeykovskaya; Umar Mahmood; Jose-Luiz Figueiredo; Jan Kitajewski; Carrie Shawber; Charles J Lightdale; Anil K Rustgi; Timothy C Wang Journal: Cancer Cell Date: 2012-01-17 Impact factor: 31.743
Authors: Li-Jyun Syu; Mohamad El-Zaatari; Kathryn A Eaton; Zhiping Liu; Manas Tetarbe; Theresa M Keeley; Joanna Pero; Jennifer Ferris; Dawn Wilbert; Ashley Kaatz; Xinlei Zheng; Xiotan Qiao; Marina Grachtchouk; Deborah L Gumucio; Juanita L Merchant; Linda C Samuelson; Andrzej A Dlugosz Journal: Am J Pathol Date: 2012-10-01 Impact factor: 4.307
Authors: Yaqing Zhang; Wei Yan; Meredith A Collins; Filip Bednar; Sabita Rakshit; Bruce R Zetter; Ben Z Stanger; Ivy Chung; Andrew D Rhim; Marina Pasca di Magliano Journal: Cancer Res Date: 2013-10-04 Impact factor: 12.701
Authors: Trevelyan R Menheniott; Louise O'Connor; Yok Teng Chionh; Jan Däbritz; Michelle Scurr; Benjamin N Rollo; Garrett Z Ng; Shelley Jacobs; Angelique Catubig; Bayzar Kurklu; Stephen Mercer; Toshinari Minamoto; David E Ong; Richard L Ferrero; James G Fox; Timothy C Wang; Philip Sutton; Louise M Judd; Andrew S Giraud Journal: J Clin Invest Date: 2016-03-14 Impact factor: 14.808