KIAA1429 promotes tumorigenesis and gefitinib resistance in lung adenocarcinoma by activating the JNK/ MAPK pathway in an m6A-dependent manner

Non-small cell lung cancer is the leading cause of cancer related mortality worldwide, and lung adenocarcinoma (LUAD) is one of the most common subtypes. The role of N6-methyladenosine (m6A) modification in tumorigenesis and drug resistance in LUAD remains unclear. In this study, we evaluated the ef...

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Published in:Drug resistance updates 2023-01, Vol.66, p.100908, Article 100908
Main Authors: Lin, Xi, Ye, Rongyi, Li, Zhiming, Zhang, Bingli, Huang, Yuji, Du, Jiaxin, Wang, Bo, Meng, Hao, Xian, Hongyi, Yang, Xingfen, Zhang, Xin, Zhong, Yizhou, Huang, Zhenlie
Format: Article
Language:English
Subjects:
Gefitinib resistance
KIAA1429
Lung adenocarcinoma (LUAD)
M6A
MAP3K2
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Summary:Non-small cell lung cancer is the leading cause of cancer related mortality worldwide, and lung adenocarcinoma (LUAD) is one of the most common subtypes. The role of N6-methyladenosine (m6A) modification in tumorigenesis and drug resistance in LUAD remains unclear. In this study, we evaluated the effects of vir-like m6A methyltransferase-associated protein (KIAA1429) depletion on proliferation, migration, invasion, and drug resistance of LUAD cells, and identified m6A-dependent downstream genes influenced by KIAA1429. We found that KIAA1429 activated Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway as a novel signaling event, which is responsible for tumorigenesis and resistance to gefitinib in LUAD cells. KIAA1429 and MAP3K2 showed high expression in LUAD patients’ tissues. Knockdown of KIAA1429 inhibited MAP3K2 expression in an m6A methylation-dependent manner, restraining the progression of LUAD cells and inhibiting growth of gefitinib-resistant HCC827 cells. KIAA1429 positively regulated MAP3K2 expression, activated JNK/ MAPK pathway, and promoted drug resistance in gefitinib-resistant HCC827 cells. We reproduced the in vitro results in nude mouse xenografted with KIAA1429 knockdown cells. Our study showed that the mechanism of m6A KIAA1429-mediated gefitinib resistance in LUAD cells occurs by activating JNK/ MAPK signaling pathway. These findings provide potential targets for molecular therapy and clinical treatment in LUAD patients with gefitinib resistance.
ISSN:1368-7646
1532-2084
DOI:10.1016/j.drup.2022.100908