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

Lu Liang ^{#  1} , Wen-Yan Xu ^{#  1} , Ao Shen ^{#  1} , Hui-Yu Cen  ¹ , Zhi-Jun Chen  ² , Lin Tan  ¹ , Ling-Min Zhang  ¹ , Yu Zhang  ¹ , Ji-Jun Fu  ¹ , Ai-Ping Qin  ¹ , Xue-Ping Lei  ¹ , Song-Pei Li  ¹ , Yu-Yan Qin  ³ , Jiong-Hua Huang  ⁴ , Xi-Yong Yu  ⁵ Affiliations

• PMID: 35388129
• DOI: 10.1038/s41401-022-00893-8

Abstract

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: EMT; MAP3K9; lung adenocarcinoma; metastasis; methylation; miR-148a-3p.