한빛사논문
- 조회843
Linyong Du 1, Zhipeng Su 2, Silu Wang 3, Ying Meng 4,5, Fei Xiao 1, Daqian Xu 4,5, Xinjian Li 6, Xu Qian 7, Su Bin Lee 8, Jong-Ho Lee 8, Zhimin Lu 4,5, Jianxin Lyu 1,9
1Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
2Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University Wenzhou, Zhejiang, 325000, China.
3Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
4Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
5Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310029, China.
6CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
7Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
8Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.
9People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
L.D. and Z.S. contributed equally to this work.
CORRESPONDING AUTHORS: Jong-Ho Lee, Zhimin Lu, Jianxin Lyu
Abstract
Tumor cells often overexpress immune checkpoint proteins, including CD47, for immune evasion. However, whether or how oncogenic activation of receptor tyrosine kinases, which are crucial drivers in tumor development, regulates CD47 expression is unknown. Here, it is demonstrated that epidermal growth factor receptor (EGFR) activation induces CD47 expression by increasing the binding of c-Src to CD47, leading to c-Src-mediated CD47 Y288 phosphorylation. This phosphorylation inhibits the interaction between the ubiquitin E3 ligase TRIM21 and CD47, thereby abrogating TRIM21-mediated CD47 K99/102 polyubiquitylation and CD47 degradation. Knock-in expression of CD47 Y288F reduces CD47 expression, increases macrophage phagocytosis of tumor cells, and inhibits brain tumor growth in mice. In contrast, knock-in expression of CD47 K99/102R elicits the opposite effects compared to CD47 Y288F expression. Importantly, CD47-SIRPα blockade with an anti-CD47 antibody treatment significantly enhances EGFR-targeted cancer therapy. In addition, CD47 expression levels in human glioblastoma (GBM) specimens correlate with EGFR and c-Src activation and aggravation of human GBM. These findings elucidate a novel mechanism underlying CD47 upregulation in EGFR-activated tumor cells and underscore the role of the EGFR-c-Src-TRIM21-CD47 signaling axis in tumor evasion and the potential to improve the current cancer therapy with a combination of CD47 blockade with EGFR-targeted remedy.
논문정보
- Research article
- 2023년 08월 (BRIC 등록일 2023-08-07)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
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