Positive feedback regulation between IL10 and EGFR promotes lung cancer formation
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Tsung-I Hsu1,2,3, Yi-Chang Wang4, Chia-Yang Hung4, Chun-Hui Yu5, Wu-Chou Su6, Wen-Chang Chang1,2,3,4,5,7, Jan-Jong Hung1,2,4,5,7
1Center for Infection Disease and Signal Research, College of Medicine, Tainan, Taiwan
2Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
3The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan
4Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
6Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
7Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
Jan-Jong Hung, e-mail: [email protected]
Keywords: IL10, Src, nucleolin, EGFR
Received: July 22, 2015 Accepted: January 29, 2016 Published: March 03, 2016
The role of IL10 in the tumorigenesis of various cancer types is still controversial. Here, we found that increased IL10 levels are correlated with a poor prognosis in lung cancer patients. Moreover, IL10 levels were significantly increased in the lungs and serum of EGFRL858R- and Kras4bG12D-induced lung cancer mice, indicating that IL10 might facilitate lung cancer tumorigenesis. IL10 knockout in EGFRL858R and Kras4bG12D mice inhibited the development of lung tumors and decreased the levels of infiltrating M2 macrophages and tumor-promoting Treg lymphocytes. We also showed that EGF increases IL10 expression by enhancing IL10 mRNA stability, and IL10 subsequently activates JAK1/STAT3, Src, PI3K/Akt, and Erk signaling pathways. Interestingly, the IL10-induced recruitment of phosphorylated Src was critical for inducing EGFR through the activation of the JAK1/STAT3 pathway, suggesting that Src and JAK1 positively regulate each other to enhance STAT3 activity. Doxycycline-induced EGFRL858R mice treated with gefitinib and anti-IL10 antibodies exhibited poor tumor formation. In conclusion, IL10 and EGFR regulate each other through positive feedback, which leads to lung cancer formation.
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