title: Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis.
abstract: Previous studies mainly focused on the role of the epidermal growth factor receptor (EGFR) in tumor cells, whereas the effects of the EGFR on immune responses has not been determined. Our study shows that the EGFR signaling pathway play a role in the regulation of regulatory T cells (Treg cells) in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently up-regulated in a tissue microarray, which was associated with worse overall survival. Additionally, in sera, tissue specimens, and effusions of lung or gastric cancer patients, up-regulated AREG protein enhanced the suppressive function of Treg cells. AREG maintained the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis in vitro and in vivo Furthermore, inhibition of EGFR by the tyrosine kinase inhibitor gefitinib restored the activity of GSK-3β and attenuated Treg cell function. β-TrCP was involved in GSK-3β-mediated Foxp3 degradation, and mass spectrometry identified Lys356as the ubiquitination site of Foxp3 by β-TrCP. These findings demonstrate the posttranslational regulation of Foxp3 expression by AREG in cancer patients through AREG/EGFR/GSK-3β signaling, which could lead to Foxp3 protein degradation in Treg cells and a potential therapeutic target for cancer treatment.
authors.affiliation: From the Departments of Thoracic Surgery.
authors.forename: Sihua
authors.initials: S
authors.lastname: Wang
authors.affiliation: Obstetrics and Gynecology, and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the Department of Cardiovascular Surgery, Central Hospital of Wuhan, Wuhan 430022, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: the Department of Cardiovascular Surgery, Central Hospital of Wuhan, Wuhan 430022, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: the Department of Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China allergyli@163.com.
authors.forename: Huabin
authors.initials: H
authors.lastname: Li
authors.affiliation: the Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and qingqing_ding@hotmail.com.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China, jiahong.xia@hust.edu.cn.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
mesh_terms: D066258:Amphiregulin / Q000276:immunology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D044844:beta-Transducin Repeat-Containing Proteins / Q000276:immunology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011799:Quinazolines; D044844:beta-Transducin Repeat-Containing Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D000077156:Gefitinib
keywords: GSK-3β; epidermal growth factor receptor (EGFR); forkhead box P3 (FOXP3); glycogen synthase kinase 3 (GSK-3); lung adenocarcinoma; phosphorylation; protein degradation; protein phosphorylation; regulatory T cells; ubiquitylation (ubiquitination)