title: Positive feedback regulation between IL10 and EGFR promotes lung cancer formation.
abstract: 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.
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Hsu
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D016753:Interleukin-10; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; IL10; Src; nucleolin