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Abstract
Growing evidence shows that granulocyte macrophage colony-stimulating factor (GM-CSF) has progression-promoting potentials in certain solid tumors, which is largely attributed to the immunomodulatory function of this cytokine in tumor niches. However, little is known about the effect of GM-CSF on cancer cells. Herein, we show that chronic exposure of colon cancer cells to GM-CSF, which harbor its receptor, leads to occurrence of epithelial to mesenchymal transition (EMT), in time and dose-dependent manners. These GM-CSF-educated cancer cells exhibit enhanced ability of motility in vitro and in vivo. Furthermore, GM-CSF stimulation renders colon cancer cells more resistant to cytotoxic agents. Mechanistic investigation reveals that MAPK/ERK signaling and EMT-inducing transcription factor ZEB1 are critical to mediate these effects of GM-CSF. In specimen of CRC patients, high-level expression of GM-CSF positively correlates with local metastases in lymph nodes. Moreover, the co-expression of GM-CSF and its receptors as well as phosphorylated ERK1/2 are observed. Thus, our study for the first time identifies a progression-promoting function of GM-CSF in colon cancer by inducing EMT.
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Details
1 Department of Immunology, Institute of Basic Medical Sciences, Beijing, P.R. China; College of Pharmacy, China Pharmaceutical University, Nanjing, P.R. China
2 Department of Pathology, Yihe Hospital, Henan University, Zhengzhou, P.R. China
3 Department of Experimental Animals, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, P.R. China
4 Department of Immunology, Institute of Basic Medical Sciences, Beijing, P.R. China
5 Graduate School, Anhui Medical University, Hefei, P.R. China
6 Department of Pathology, University of Michigan, Ann Arbor, MI, USA
7 College of Pharmacy, China Pharmaceutical University, Nanjing, P.R. China; Department of Environment and Pharmacy, Institute of Health and Environmental Medicine, Tianjin, P.R. China