期刊
CANCER LETTERS
卷 433, 期 -, 页码 186-198出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.07.002
关键词
USP22; Deubiquitination; EGFR degradation; EGFR-TKIs resistance; EGFR-mutant lung adenocarcinoma
类别
资金
- National Natural Science Fund of China [81572276, 81573001, 81673024, 81672931]
- National Natural Science Fund Youth of Fund of China [81501960, 81602717]
- 60th Postdoctoral Natural Science Fund of China [2016M601442]
- 7th Postdoctoral Special Science-Research Fund of Heilongjiang Province [LBH-TZ1616]
- Haiyan Fund of Harbin Medical University Cancer Hospital grant [JJMS2016-02]
- Overseas Scientific Research Fund of Education Department of Heilongjiang Province grant [1254HQ015]
As a newly discovered deubiquitinating enzyme, ubiquitin-specific protease 22 (USP22) is predictive of therapeutic outcomes in individual cancer patients. However, its clinical effects on malignancy and its roles in conferring resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in lung adenocarcinoma (ADC) remain largely unknown. Here, we showed that USP22 promotes cell proliferation, migration and invasion, and contributes to resistance to EGFR-TKIs in EGFR mutant lung ADC cells. Mechanistically, USP22 deubiquitinates EGFR localized on late endosomes, prevents ubiquitination mediated EGFR degradation and enhances recycling of EGFR after EGF stimulation. Additionally, USP22 sustained the activation of multiple EGFR downstream signaling pathways, including STAT3, AKT/mTOR and MEK/ERK pathways, in lung ADC cell lines H1975 and PC9. Furthermore, USP22 stabilizes EGFR protein expression, which correlates with USP22 expression in EGFR-mutant lung ADC patient samples. We are the first to demonstrate that silencing USP22 counteracts EGFR-TKIs resistance both in vitro and in vivo. We propose USP22 as a potential therapeutic target for EGFR-TKIs-resistant lung ADC.
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