Department of Pediatrics, Cancer Hospital of the Harbin Medical UniversityHarbinP.R. China.
Department of Thoracic Surgery, Cancer Hospital of the Harbin Medical UniversityHarbinP.R. China.
Oncol Res. 2018 Apr 10;26(3):385-400. doi: 10.3727/096504017X14973124850905. Epub 2017 Jun 13.
Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.
许多研究表明，miR-138 在包括非小细胞肺癌（NSCLC）在内的多种癌症中下调。然而，miR-138 在 NSCLC 中的确切机制尚未得到很好的阐明。在这项研究中，我们研究了 miR-138 在 NSCLC 细胞系中的生物学功能和分子机制，探讨其是否可能成为未来 NSCLC 的治疗性生物标志物。在我们的研究中，我们发现 miR-138 在 NSCLC 组织和细胞系中下调。此外，miR-138 水平低与 NSCLC 组织和细胞系中 SOX4 表达增加有关。上调 miR-138 显著抑制 NSCLC 细胞的增殖。此外，过表达 miR-138 抑制了 NSCLC 细胞的侵袭和 EMT。然而，下调 miR-138 促进了 NSCLC 细胞的生长和转移。生物信息学分析预测 SOX4 是 miR-138 的一个潜在靶基因。接下来，荧光素酶报告基因实验证实 miR-138 可以直接靶向 SOX4。与 miR-138 的作用一致，siRNA 下调 SOX4 抑制了 NSCLC 细胞的增殖、侵袭和 EMT。NSCLC 细胞中 SOX4 的过表达部分逆转了 miR-138 模拟物的作用。此外，SOX4 表达的降低可以通过上调 p53 增加 miR-138 的水平。通过 SOX4/p53 反馈环，引入 miR-138 可显著抑制 NSCLC 细胞的生长、侵袭和 EMT。
