Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9

Lu Liang1, Wen-yan Xu1, Ao Shen1, Hui-yu Cen1, Zhi-jun Chen2, Lin Tan1, Ling-min Zhang1, Yu Zhang1, Ji-jun Fu1, Ai-ping Qin1, Xue-ping Lei1, Song-pei Li1, Yu-yan Qin1, Jiong-hua Huang3, Xi-yong Yu1
1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
2 Department of Medical Imaging, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
3 Department of Cardiovascular Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
Correspondence to: Yu-yan Qin:, Jiong-hua Huang:, Xi-yong Yu:,
DOI: 10.1038/s41401-022-00893-8
Received: 3 October 2021
Accepted: 21 February 2022
Advance online: 6 April 2022


Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.
Keywords: methylation; miR-148a-3p; MAP3K9; lung adenocarcinoma; metastasis; EMT

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