Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9
Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9
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DOI：
10.1038/s41401-022-00893-8
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发表时间：
2022-04-06
影响因子：
8.2
通讯作者：
Yu, Xi-yong
中科院分区：
文献类型：
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作者：
Liang, Lu;Xu, Wen-yan;Yu, Xi-yong
肺腺癌(LUAD)是非小细胞肺癌的主要亚型，具有高转移率和高死亡率的特点。有证据表明，某些microRNAs(MiRNAs)可能作为癌基因或抑癌基因，导致恶性肿瘤的发生和发展。为了更好地了解miRNA甲基化在LUAD进展和临床预后中的分子机制，我们研究了miR-148A-3p甲基化与LUAD临床特征的相关性。在LUAD细胞系和患者的肿瘤组织中，miR-148A-3p的表达显著下调，而miR-148A-3p的启动子甲基化显著增加。重要的是，miR-148A-3p高甲基化与淋巴结转移密切相关。我们证明MAP3K9是miR-148A-3p的靶点，并且MAP3K9在LUAD细胞系和临床肿瘤组织中的水平都显著升高。在A549和NCI-H1299细胞中，miR-148A-3p的过表达或MAP3K9的沉默显著抑制了细胞的生长、迁移、侵袭和细胞骨架重组，同时抑制了上皮向间充质的转变。在裸鼠移植瘤实验中，我们发现miR-148A-3p过表达能有效地抑制肿瘤的生长。综上所述，miR-148A-3p启动子甲基化相关的降低可能通过靶向MAP3K9而导致肺癌转移。本研究提示miR-148A-3p和MAP3K9可能成为治疗LUAD的新靶点，具有潜在的临床应用价值。
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.