Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats
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Kiyoshi Terawaki1,2, Yohei Kashiwase1,3, Miaki Uzu1, Miki Nonaka1, Yumi Sawada1, Kanako Miyano1, Yoshikazu Higami3, Kazuyoshi Yanagihara4, Masahiro Yamamoto2 and Yasuhito Uezono1,5,6
1Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-Ku, Tokyo 104-0045, Japan
2Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., Inashiki-Gun, Ibaraki 300-1192, Japan
3Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
4Division of Biomarker Discovery, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
5Division of Supportive Care Research, Exploratory Oncology Research & Clinica l Trial Center, National Cancer Center, Chuo-Ku, Tokyo 104-0045, Japan
6Innovation Center for Supportive, Palliative and Phychosocial Care, National Cancer Center Hospital, Chuo-Ku, Tokyo 104-0045, Japan
Yasuhito Uezono, email: [email protected]
Keywords: cancer cachexia; anorexia; gastric cancer; leukemia inhibitory factor; toll-like receptor
Received: February 28, 2018 Accepted: September 01, 2018 Published: October 05, 2018
Cancer cachexia is highly prevalent in gastric cancer patients and characterized by decreased food consumption and body weight. We previously created a rat model of cancer cachexia using MKN45cl85 and 85As2 cells derived from human gastric cancer. The 85As2 cells induced cachexia more potently compared to MKN45cl85 cells. To clarify the mechanism underlying the difference in the cachexia-inducing ability of these cells, we conducted DNA microarray analysis, focusing on cell proliferation and the production of leukemia inhibitory factor (LIF), a cachexia-inducing factor. The plasma human LIF levels of 85As2-induced cachexic rats increased as symptoms worsened, whereas the plasma levels of MKNcl85 were low. 85As2 cells displayed more genetic changes compared to MKN45cl85 cells, which were related to Toll-like receptor (TLR) 4/5 signaling. Stimulation of both cells with TLR4 (lipopolysaccharide) or TLR5 (flagellin) agonists did not affect proliferation. However, in 82As2 cells, LIF production was significantly increased by stimulation with TLR5, which was suppressed by an inhibitor of interleukin-1 receptor-associated kinase-1/4, which are important factors in the TLR5 signaling pathway. The increase in LIF production resulting from activation of the TLR5 signaling pathway may contribute to the cachexia-inducing ability of 85As2 cells.
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