Abstract
Understanding the molecular mechanism by which epithelial mesenchymal transition (EMT)-mediated cancer metastasis and how microRNA (miRNA) regulates lung cancer progression via Twist1-activated EMT may provide potential therapeutic targets for cancer therapy. Here we found that miR-33a, an intronic miRNA located within the sterol regulatory element-binding protein 2 (SREBP-2) gene, is expressed at low levels in metastatic non-small cell lung cancer (NSCLC) cells and is inversely correlated with Twist1 expression. Conversely, miR-33a knockdown induces EMT and miR-33a overexpression blocks EMT by regulating of Twist1 expression in NSCLC cells. Bioinformatical prediction and luciferase reporter assay confirm that Twist1 is a direct target of miR-33a. Additionally, Twist1 knockdown blocks EMT-related metastasis and forced expression of miR-33a inhibits lung cancer metastasis in a xenograft animal model. Clinically, miR-33a is found to be at low levels in NSCLC patients and down-regulation of miR-33a predicts a poor prognosis. These findings suggest that miR-33a targets Twist1 and inhibits invasion and metastasis in NSCLC. Thus, miR-33a might be a potential prognostic marker and of therapeutic relevance for NSCLC metastasis intervention.
Highlights
Sterol regulatory element-binding protein 2 (SREBP-2) gene, was originally found to regulate cholesterol metabolism[10,11], and to control cell cycle[12,13]
A given miRNA may have multiple target genes that are involved in lung cancer progression; most of the details of the epithelial to mesenchymal transition (EMT)-dependent metastatic mechanism have not been elucidated
The transcription factor Twist[1] and the EMT-associated miRNAs are reported to be associated with cancer metastasis[19,20]
Summary
Sterol regulatory element-binding protein 2 (SREBP-2) gene, was originally found to regulate cholesterol metabolism[10,11], and to control cell cycle[12,13]. A given miRNA may represent pleiotropic effects on cellular functions, whether miR-33a is directly involved in EMT and metastasis in NSCLC has not been reported. MiRNAs may act as critical regulators in cancer metastasis, the mechanism how miR-33a regulates metastasis by targeting the EMT-relevant transcriptional factors was unknown at the onset of this study. We provide the first demonstration that miR-33a modulates EMT in NSCLC cells and targets Twist[1], an EMT-inducing transcription factor. MiR-33a suppresses NSCLC metastasis in vivo in a xenograft mouse model. Our findings suggest that miR-33a could be used as a potential therapeutic RNA mimic (miRNA replacement) for the treatment of patients with the advanced NSCLC
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