406915

MIR128-1

Deregulated expression of miRNAs contributes to the development of osteosarcoma. The present study was to evaluate the level of miR-128 and integrin alpha2 (ITGA2) in osteosarcoma tissues and cells. We further investigated the molecular mechanisms of miR-128 and ITGA2 in osteosarcoma cell lines. In the present study, we found that miR-128 expression was down-regulated in osteosarcoma tissues and MG-63, U2OS, and SAOS-2 cells (all p < 0.001). By contrast, ITGA2 was up-regulated. Furthermore, we found that miR-128 overexpression suppressed cell migration and invasion of MG-63 cells. Mechanically, miR-128 overexpression inhibited epithelial-mesenchymal transition (EMT) of MG-63 cells. Importantly, we identified that the 3'-untranslated region (3'-UTR) of ITGA2 was a direct target of miR-128. Luciferase reporter assays confirmed that miR-128 binding to the 3'-UTR regions of ITGA2 inhibited the expression of ITGA2 in MG-63 cells. At the same time, overexpressed ITGA2 also reversed EMT inhibited by miR-128. In conclusion, this study suggested that high miR-128 expression suppressed osteosarcoma cell migration, invasion, and EMT development through targeting ITGA2, which may be recommended as a therapeutic target for osteosarcoma.

miR-128 is expressed in various tumors, but its expression and function in gastric cancer have not been defined. Thus, the goal of this study was to characterize miR-128 in gastric cancer. We found first that miR-128 is down-regulated in gastric cancer cell lines and tissues, and this dysregulation is correlated with DNA methylation and the transcription factor SNAIL. Using prediction tools, western blotting, and luciferase reporter assays, we found that Bmi-1 was the direct target of miR-128. Additionally, overexpression of miR-128 inhibited gastric cancer cell migration, invasion, and proliferation by targeting Bmi-1 in vitro and in vivo. We also documented, with receiver operating characteristic curves and Kaplan-Meier survival analysis, that miR-128 and Bmi-1 may be useful markers for diagnosing and estimating the prognosis of gastric cancer patients. As the epithelial-to-mesenchymal transition is an important mechanism associated with cancer invasion and metastasis, we inferred that miR-128 could regulate this mechanism in gastric cancer. In fact, we found that miR-128 could reverse epithelial-to-mesenchymal transition induced by Bmi-1 via the PI3K/AKT pathway. Because SNAIL also acts as a mesenchymal marker, our findings identified a novel positive feedback loop in which the transcription factor SNAIL curbs the expression of miR-128, and then down-regulated miR-128 promotes the expression of Bmi-1; finally, overexpression of Bmi-1 drives the epithelial-to-mesenchymal transition process via the PI3K/AKT pathway, and the expression of SNAIL is up-regulated.

cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/beta-catenin and TGF-beta pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/beta-catenin and TGF-beta activities. Notably, correlations among miR-128-3p levels, activated beta-catenin and TGF-beta signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.