Abstract
BackgroundThe metastatic cascade is a complex and multistep process with many potential barriers. Recently, miR-193a has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-oncogenic activity in non-small cell lung cancers (NSCLC) is not fully elucidated.MethodsThe expressions of miR-193a (miR-193a-5p) in human lung cancer tissues and cell lines were detected by real-time PCR. Dual-luciferase reporter assay was used to identify the direct target of miR-193a. Cell proliferation, apoptosis, and metastasis were assessed by CCK-8, flow cytometry, and Transwell assay, respectively.ResultsThe expression of miR-193a in lung cancer tissues was decreased comparing to adjacent non-tumor tissues due to DNA hypermethylation in lung cancer tissues. Ectopic expression of miR-193a inhibited cell proliferation, colony formation, migration, and invasion in A549 and H1299 cells. Moreover, overexpression of miR-193a partially reversed tumor growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) in NSCLC cells. Mechanistically, miR-193a reduced the expression of WT1, which negatively regulated the protein level of E-cadherin, suggesting that miR-193a might prevent EMT via modulating WT1-E-cadherin axis. Importantly, knockdown of WT1 resembled the anti-cancer activity by miR-193a and overexpression of WT1 partially reversed miR-193a-induced anti-cancer activity, indicating that WT1 plays an important role in miR-193a-induced anti-cancer activity. Finally, overexpression of miR-193a decreased the growth of tumor xenografts in mice.ConclusionCollectively, our results have revealed an important role of miR-193a-WT1-E-cadherin axis in metastasis, demonstrated an important molecular cue for EMT, and suggested a therapeutic strategy of restoring miR-193a expression in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0450-8) contains supplementary material, which is available to authorized users.
Highlights
The metastatic cascade is a complex and multistep process with many potential barriers
Downregulation of miR-193a in lung cancer tissues To investigate the role of miR-193a in lung cancer cells, the expression of miR-193a was detected in several lung cancer cell lines and normal lung epithelial cell line BEAS-2B
The relationship between miR-193a expression levels and clinicopathological characteristics of the non-small cell lung cancers (NSCLC) patients were indicated in Additional file 1: Table S1
Summary
The metastatic cascade is a complex and multistep process with many potential barriers. Metastasis is the leading reason for the resultant mortality in more than 90 % of patients with cancer, including lung cancer. Metastasis is a complex process in which the metastatic potential of NSCLC cells is influenced by cell-intrinsic identities and extrinsic microenvironment factors. Metastasis is associated with epithelialmesenchymal transition (EMT), a biologic process during which epithelial cells acquire new features of mesenchyme [5]. E-cadherin is inhibited by many transcript factors such as Snail, ZEB1/2, and Slug, which are induced by multiple signaling pathways including Wnt, TGF-β, and Notch [7, 8]. TGF-β promotes tumor progression through enhancing migration and invasion, and induces EMT through inhibiting the expressions of Snail and Slug [9]
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