MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A.
MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A.
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MicroRNA-101 通过靶向 DNA 甲基转移酶 3A，通过 PTEN/AKT 信号通路抑制肺癌的进展。
DOI：
10.3892/ol.2016.5423
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发表时间：
2017-01
期刊：
影响因子：
2.9
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Wang L;Yao J;Sun H;He K;Tong D;Song T;Huang C
众所周知，通过DNA甲基化导致的关键肿瘤抑制基因的转录沉默是肺癌发生的一个基本过程。然而，microRNAs（miRNAs）参与恢复肺癌中异常DNA甲基化模式的机制尚不清楚。因此，由于miRNA-101与DNA甲基转移酶3A（DNMT 3A）的3′-非翻译区互补，我们研究了miRNA-101是否可以恢复肺癌细胞系中正常的DNA甲基化模式。生物信息学研究表明，DNMT 3A是miR-101的主要靶点。此外，miR-101的过表达下调DNMT 3A。使用甲基化特异性聚合酶链反应分析，我们证明了磷酸酶和张力蛋白同源物（PTEN）启动子的甲基化在转染miR-101的A549细胞中减少，但在转染对照中没有。此外，miR-101过表达和DNMT 3A沉默抑制肺细胞增殖和S/G2转换，并通过PTEN/AKT途径增加体外细胞凋亡。此外，我们在用miR-101抑制剂转染的A549细胞中观察到相反的现象。随后的研究显示，miR-101的过表达显著抑制了裸鼠异种移植模型中A549细胞的致瘤性。这些结果表明，miR-101通过靶向肺细胞中的DNMT 3A通过PTEN/AKT信号通路影响肺癌进展，表明miR-101可能是肺癌治疗中的新的潜在治疗策略。
It is well established that transcriptional silencing of critical tumor suppressor genes by DNA methylation is a fundamental process in the initiation of lung cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in lung cancer is not well understood. Therefore, and since miRNA-101 is complementary to the 3′-untranslated region of DNA methyltransferase 3A (DNMT3A), we investigated whether miRNA-101 could restore normal DNA methylation patterns in lung cancer cell lines. Bioinformatics has indicated that DNMT3A is a major target of miR-101. In addition, the overexpression of miR-101 downregulates DNMT3A. Using a methylation-specific polymerase chain reaction assay, we demonstrated that methylation of the phosphatase and tensin homolog (PTEN) promoter was reduced in A549 cells transfected with miR-101, but not in the transfected control. Furthermore, overexpression of miR-101 and silencing of DNMT3A suppressed lung cell proliferation and S/G2 transition, and increased apoptosis through the PTEN/AKT pathway in vitro. Furthermore, we observed the opposite phenomenon in A549 cells transfected with a miR-101 inhibitor. Subsequent investigation revealed that overexpression of miR-101 significantly inhibited the tumorigenicity of A549 cells in a nude mouse xenograft model. These results demonstrate that miR-101 affects lung cancer progression through the PTEN/AKT signaling pathway by targeting DNMT3A in lung cells, suggesting that miR-101 may be a novel potential therapeutic strategy in lung cancer treatment.