DUSP22 inhibits lung tumorigenesis by suppression of EGFR/c-Met signaling
Journal
Cell Death Discovery
Series/Report No.
Cell Death Discovery
Journal Volume
10
Journal Issue
1
Start Page
Article number: 285
ISSN
2058-7716
Date Issued
2024-06-14
Author(s)
Hsiao-Han Lin
Cheng-Wei Chang
Yu-Ting Liao
Shauh-Der Yeh
Hsiu-Ping Lin
Hui-Min Ho
Chantal Hoi-Yin Cheung
Yi-Rong Chen
Yu-Wen Su
Li-Mei Chen
Tse-Hua Tan
Wen-Jye Lin
DOI
10.1038/s41420-024-02038-8
Abstract
DUSP22, an atypical dual-specificity phosphatase enzyme, plays a significant role in regulating multiple kinase signaling pathways by dephosphorylation. Our study demonstrated that decreased DUSP22 expression is associated with shorter disease-free survival, advanced TNM (tumor, lymph nodes, and metastasis), cancer stage, and higher tumor grade in lung adenocarcinoma (LUAD) patients. Exogenous DUSP22 expression reduces the colony-forming capacity of lung cancer cells and inhibits xenograft tumor growth primarily by targeting EGFR and suppressing its activity through dephosphorylation. Knockdown of DUSP22 using shRNA enhances EGFR dependency in HCC827 lung cancer cells and increases sensitivity to gefitinib, an EGFR inhibitor. Consistently, genetic deletion of DUSP22 enhances EGFRdel (exon 19 deletion)-driven lung tumorigenesis and elevates EGFR activity. Pharmacological inhibition of DUSP22 activates EGFR, ERK1/2, and upregulates downstream PD-L1 expression. Additionally, lentiviral deletion of DUSP22 by shRNA enhances lung cancer cell migration through EGFR/c-Met and PD-L1-dependent pathways. Gefitinib, an EGFR inhibitor, mechanistically suppresses migration induced by DUSP22 deletion and inhibits c-Met activity. Furthermore, cabozantinib, a c-Met inhibitor, reduces migration and attenuates EGFR activation caused by DUSP22 deletion. Collectively, our findings support the hypothesis that loss of DUSP22 function in lung cancer cells confers a survival advantage by augmenting EGFR signaling, leading to increased activation of downstream c-Met, ERK1/2, and PD-L1 axis, ultimately contributing to the progression of advanced lung cancer.
Publisher
Springer Science and Business Media LLC
Type
journal article