Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Aging (Albany NY). 2022 Apr 25;14(8):3540-3553. doi: 10.18632/aging.204028.
MicroRNAs (miRNAs) have been revealed to play a crucial role in oncogenesis of esophageal squamous cell carcinoma (ESCC). However, the biological role of miR-181a-5p in ESCC is currently less explored. The current study was designed to assess whether miR-181a-5p affects ESCC progression and further investigate relevant underlying mechanisms. Based on the data of GSE161533, GSE17351, GSE75241 and GSE67269 downloaded from GEO database, MAP2K1 (MEK1) was revealed to be one overlapping gene of the top 300 DGEs. Additionally, using the predicting software, miR-181a-5p was projected as the presumed target miRNA. Immunohistochemical staining and RT-qPCR research revealed that miR-181a-5p expression was decreased in human tumor tissues relative to surrounding peri-cancerous tissues. In an experiment, miR-181a-5p mimics could inhibit tumor growth and metastasis of ESCC. Gene expression profiles in combination with gene ontology (GO) and KEGG pathway analysis revealed that MAP2K1 (MEK1) gene and ERK-MMP pathway were implicated in ESCC progression. MiR-181a-5p mimics inhibited the activity of p-ERK1/2, MMP2 and MMP9 , as shown by Western blotting and immunohistochemistry labeling. There were no variations in the expression of p-P38 and p-JNK proteins. Additionally, miR-181a-5p mimics lowered p-ERK1/2, MMP2 and MMP9 levels in ECA109 cells, which were restored by MEK1-OE lentivirus. MEK1-OE Lentivirus significantly reversed the function induced by miR-181a-5p mimics in ECA109 cells. Moreover, further investigation indicated that the capability of migration, invasion and proliferation was repressed by miR-181a-5p mimics in ECA109 cells. In short, repressed ERK-MMP pathway mediated by miR-181a-5p can inhibit cell migration, invasion and proliferation by targeting MAP2K1 (MEK1) in ESCC.
微小 RNA（miRNAs）已被证明在食管鳞状细胞癌（ESCC）的发生中发挥关键作用。然而，miR-181a-5p 在 ESCC 中的生物学作用目前研究较少。本研究旨在评估 miR-181a-5p 是否影响 ESCC 进展，并进一步探讨相关的潜在机制。
基于从 GEO 数据库下载的 GSE161533、GSE17351、GSE75241 和 GSE67269 中的数据，发现 MAP2K1（MEK1）是 top300 DGEs 的一个重叠基因。此外，使用预测软件，预测 miR-181a-5p 是假定的靶 miRNA。免疫组织化学染色和 RT-qPCR 研究表明，miR-181a-5p 在人肿瘤组织中的表达相对于周围癌旁组织降低。在一项实验中，miR-181a-5p 模拟物可以抑制 ESCC 的肿瘤生长和转移。
基因表达谱结合基因本体（GO）和 KEGG 通路分析表明，MAP2K1（MEK1）基因和 ERK-MMP 通路参与 ESCC 进展。Western blot 和免疫组织化学标记显示，miR-181a-5p 模拟物抑制 p-ERK1/2、MMP2 和 MMP9 的活性。p-P38 和 p-JNK 蛋白的表达没有变化。此外，miR-181a-5p 模拟物降低了 ECA109 细胞中 p-ERK1/2、MMP2 和 MMP9 的水平，而 MEK1-OE 慢病毒则恢复了这些水平。MEK1-OE 慢病毒显著逆转了 miR-181a-5p 模拟物在 ECA109 细胞中的作用。此外，进一步的研究表明，miR-181a-5p 模拟物抑制了 ECA109 细胞的迁移、侵袭和增殖能力。
总之，miR-181a-5p 抑制的 ERK-MMP 通路通过靶向 MAP2K1（MEK1）可以抑制 ESCC 中细胞的迁移、侵袭和增殖。
