MircoRNA-33a inhibits epithelial-to-mesenchymal transition and metastasis and could be a prognostic marker in non-small cell lung cancer.
Bottom Line: 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.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.
Affiliation: Institute of Biochemistry and Molecular Biology.
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.
No MeSH data available.
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Mentions: To further investigate the clinical significance of miR-33a expression in NSCLC patients, the expression levels of miR-33a were measured using qRT-PCR analysis and the survival curves were calculated by the Kaplan-Meier method. The influence of each variable on survival was examined by the Cox multivariate regression analysis. Compared with non-tumor tissues, the expression level of miR-33a was significantly decreased in NSCLC tissues (2.07 ± 0.08 versus 6.79 ± 0.12, P < 0.001, Fig. 7A). The expression level of miR-33a was positively correlated with grade (P = 0.002, Supplementary Table S1). In addition, NSCLC patients with advanced histologic grade (local invasion T3-4) had obvious shorter overall survival (OS) than patients with low grade (T1-2) (P = 0.0227, Fig. 7B). A significant difference was that NSCLC patients with high miR-33a expression level had remarkable longer OS than patients with low miR-33a expression level (P = 0.0023, Fig. 7C). Furthermore, we found that low miR-33a expression (P = 0.008) and advanced histologic grade (P = 0.004) were independent prognostic parameters indicating poor prognosis for NSCLC patients (Supplementary Table S2). Our results show that the decreased expression of miR-33a may be associated with malignant tumor progression and poor prognosis in NSCLC patients, suggesting that miR-33a may be a novel and valuable marker for predicting the clinical outcome of NSCLC patients.
No MeSH data available.