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MiR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal.

ABSTRACT: Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene.Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities.Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.

SUBMITTER: Lulli V

PROVIDER: S-EPMC4741927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis. Materials and Methods:qRT-PCR was taken to detect circLARP4 and miR-135b expressions. MTT assay, ?transwell invasion assay and flow cytometry analysis were applied to evaluate cell proliferation, invasion and apoptosis, respectively. Glycolysis was assessed by measuring hexokinase2 (HK2) expression, glucose consumption and lactate production. Association between circLARP4 and miR-135a was examined by luciferase reporter and RIP assays. The changes of the phosphatase and tension homolog (PTEN)/protein kinase B (AKT)/hypoxia-inducible factor-1? (HIF-1?) pathway were evaluated by Western blot. The nude mouse xenograft models were applied to verify the regulation of circLARP4 in vivo. Results:CircLARP4 was decreased in NSCLC tissues and cells. CircLARP4 overexpression blocked cell proliferation and invasion, and facilitated apoptosis in NSCLC cells. Meanwhile, circLARP4 overexpression suppressed glycolysis in NSCLC cells, as evidenced by the reduced HK2, glucose consumption and lactate production levels. Further analyses proved a downregulation of miR-135b by circLARP4 in a ceRNA-dependent manner in NSCLC cells. CircLARP4-mediated tumor? suppression on NSCLC progression was partially overturned by overexpressing miR-135b. Moreover, we confirmed that circLARP4 had antitumor effect on xen?ograft tumors and downregulated miR-135b. Furthermore, circLARP4 overexpression inhibited the PTEN/AKT/HIF-1? pathway in NSCLC cells and xenograft tumors by downregulating miR-135b. Conclusion:Our findings suggested that ?circLARP4 suppressed NSCLC progression by sponging miR-135b through inactivation of the PTEN/AKT/HIF-1? pathway, which broadens our understanding concerning the roles of circLARP4 in NSCLC tumorigenesis.

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MiR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal.

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