RESUMEN
Emerging evidence has shown that cancer stem cells (CSCs) are the cellular determinants to promote cancer invasion and metastasis. However, the mechanism underlying CSC invasion remains unknown. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression, and their expressions are often dysregulated in cancers. In the present study, we demonstrated that two functionally related microRNAs, miR-20a and -106a (miR-20a/106a), were capable of enhancing the invasiveness of CD133(+) glioma stem cells (GSCs) isolated from both glioblastoma cell line U87 and primary human glioma specimens. We found that the level of miR-20a/106a in GSCs was significantly higher than that in the committed CD133(-) glioma cells, and correlated with the invasive capability of GSCs. By bioinformatic analysis, we identified tissue inhibitor of metalloproteinases-2 (TIMP-2) as one of the miR-20a/106a-targeted genes. TIMP-2 level correlated inversely with miR-20/106 expression. Directly targeting by miR-20a/106a on 3'-untranslation region (3'-UTR) of TIMP-2 mRNA was confirmed by 3'-UTR dual-luciferase reporter assay. Knockdown of miR-20a/106a in GSCs increased endogenous TIMP-2 protein abundance, thereby inhibiting GSC invasion. We also found that Nordy, a synthetic lipoxygenase inhibitor, inhibited GSC invasiveness by elevating the expression of TIMP-2 via downregulation of miR-20a/106a. Our results indicate that miR-20a/106a has a key role in GSC invasion and may serve as targets for treatment of glioblastoma.
Asunto(s)
Neoplasias Encefálicas/patología , Glioblastoma/patología , MicroARNs/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/fisiología , Antígeno AC133 , Animales , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/metabolismo , Humanos , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Masoprocol/análogos & derivados , Masoprocol/farmacología , Ratones , Ratones Desnudos , MicroARNs/biosíntesis , MicroARNs/genética , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Trasplante de Neoplasias , Células Madre Neoplásicas , Péptidos/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Trasplante HeterólogoRESUMEN
A successful experiment with a physical model requires necessary conditions of similarity. This study presents an experimental method with a semi-scale physical model. The model is used to monitor and verify soil conservation by check dams in a small watershed on the Loess Plateau of China. During experiments, the model-prototype ratio of geomorphic variables was kept constant under each rainfall event. Consequently, experimental data are available for verification of soil erosion processes in the field and for predicting soil loss in a model watershed with check dams. Thus, it can predict the amount of soil loss in a catchment. This study also mentions four criteria: similarities of watershed geometry, grain size and bare land, Froude number (Fr) for rainfall event, and soil erosion in downscaled models. The efficacy of the proposed method was confirmed using these criteria in two different downscaled model experiments. The B-Model, a large scale model, simulates watershed prototype. The two small scale models, D(a) and D(b), have different erosion rates, but are the same size. These two models simulate hydraulic processes in the B-Model. Experiment results show that while soil loss in the small scale models was converted by multiplying the soil loss scale number, it was very close to that of the B-Model. Obviously, with a semi-scale physical model, experiments are available to verify and predict soil loss in a small watershed area with check dam system on the Loess Plateau, China.