Abstract
BackgroundGlioma is the most prevalent malignant tumor in human central nervous systems. Recently, the development of resistance to radiotherapy in glioma patients markedly vitiates the therapy outcome. MiR-153-3p has been reported to be closely correlated with tumor progression, but its effect and molecular mechanism underlying radioresistance remains unclear in glioma.MethodsThe expression of miR-153-3p was determined in radioresistant glioma clinical specimens as well as glioma cell lines exposed to irradiation (IR) using quantitative real-time PCR. Cell viability, proliferation and apoptosis were then evaluated by MTT assay, colony formation assay, Flow cytometry analysis and caspase-3 activity assay in glioma cells (U87 and U251). Tumor forming was evaluated by nude mice model in vivo. TUNEL staining was used to detect cell apoptosis in nude mice model. The target genes of miR-153-3p were predicted and validated using integrated bioinformatics analysis and a luciferase reporter assay.ResultsHere, we found that miR-153-3p was down-regulated in radioresistant glioma clinical specimens as well as glioma cell lines (U87 and U251) exposed to IR. Enhanced expression of miR-153-3p promoted the radiosensitivity, promoted apoptosis and elevated caspase-3 activity in glioma cells in vitro, as well as the radiosensitivity in U251 cell mouse xenografs in vivo. Mechanically, B cell lymphoma-2 gene (BCL2) was identified as the direct and functional target of miR-153-3p. Moreover, restoration of BCL2 expression reversed miR-153-3p-induced increase of radiosensitivity, apoptosis and caspase-3 activity in U251 cells in vitro. In addition, clinical data indicated that the expression of miR-153-3p was significantly negatively associated with BCL2 in radioresistance of glioma samples.ConclusionsOur findings suggest that miR-153-3p is a potential target to enhance the effect of radiosensitivity on glioma cells, thus representing a new potential therapeutic target for glioma.
Highlights
Glioma is the most prevalent malignant tumor in human central nervous systems
Tissues samples Glioma patients (n = 45, 34 male and 11 females, median age = 54 years, range, 40–64 years) were included into this study, who underwent surgery at the Liaoning Cancer Hospital & Institute (Liaoning, China) after histopathological confirmation (WHO criteria). These patients were treated with radiotherapy for over 6 months and classified into radiosensitive (n = 25) and radioresistant (n = 20) groups based on radiosensitivity index (RSI) values (RSI index > 0.5 means radioresistant) as previously reported [23]
MiR‐153‐3p was down‐regulated in radioresistant glioma tissues and cells in response to IR MiR-153-3p has been reported to be a tumor suppressor, but whether it functions as a responder to IR remains unclear
Summary
Glioma is the most prevalent malignant tumor in human central nervous systems. Recently, the development of resistance to radiotherapy in glioma patients markedly vitiates the therapy outcome. MiR-153-3p has been reported to be closely correlated with tumor progression, but its effect and molecular mechanism underlying radioresistance remains unclear in glioma. Glioma is the one of most common primary malignancies that arises from glial or precursor cells occurring in brain and central nervous system [1]. These tumors exhibit extensive heterogeneity and consist of multiple different histological types, including anaplastic astrocytoma, glioblastoma multiforme and oligodendroglioma [2]. Chen et al [15] revealed that miR-153-3p was correlated with radioresistant genes in non-small cell lung cancer when screening of miRNA profiles through GO analysis and pathway analysis. The roles and molecular mechanisms of miR-153-3p involved in radio-resistance and progression of glioma remain undefined
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