miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway

Abstract

BackgroundChemoresistance to temozolomide (TMZ) is a major challenge in the treatment of glioblastoma (GBM). We previously found that miR-519a functions as a tumor suppressor in glioma by targeting the signal transducer and activator of transcription 3 (STAT3)-mediated autophagy oncogenic pathway. Here, we investigated the effects of miR-519a on TMZ chemosensitivity and autophagy in GBM cells. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.MethodsIn the present study, two stable TMZ-resistant GBM cell lines were successfully generated by exposure of parental cells to a gradually increasing TMZ concentration. After transfecting U87-MG/TMZ and U87-MG cells with miR-519a mimic or inhibitor, a series of biochemical assays such as MTT, apoptosis, and colony formation were performed to determine the chemosensitive response to TMZ. The autophagy levels in GBM cells were detected by transmission electron microscopy, LC3B protein immunofluorescence, and Western blotting analysis. Stable knockdown and overexpression of miR-519a in GBM cells were established using lentivirus. A xenograft nude mouse model and in situ brain model were used to examine the in vivo effects of miR-519a. Tumor tissue samples were collected from 48 patients with GBM and were used to assess the relationship between miR-519a and STAT3 expression.ResultsTMZ treatment significantly upregulated miR-519a in U87-MG cells but not in U87-MG/TMZ cells. Moreover, the expression of miR-519a and baseline autophagy levels was lower in U87-MG/TMZ cells as compared to U87-MG cells. miR-519a dramatically enhanced TMZ-induced autophagy and apoptotic cell death in U87-MG/TMZ cells, while inhibition of miR-519a promoted TMZ resistance and reduced TMZ-induced autophagy in U87-MG cells. Furthermore, miR-519a induced autophagy through modification of STAT3 expression. The in vivo results showed that miR-519a can enhance apoptosis and sensitized GBM to TMZ treatment by promoting autophagy and targeting the STAT3/Bcl-2/Beclin-1 pathway. In human GBM tissues, we found an inverse correlation between miR-519a and STAT3 expression.ConclusionsOur results suggested that miR-519a increased the sensitivity of GBM cells to TMZ therapy. The positive effects of miR-519a may be mediated through autophagy. In addition, miR-519a overexpression can induce autophagy by inhibiting STAT3/Bcl-2 pathway. Therefore, a combination of miR-519a and TMZ may represent an effective therapeutic strategy in GBM.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0618-0) contains supplementary material, which is available to authorized users.

Long noncoding RNA growth arrest‐specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR‐dependent manner

“…Analogous with our results, knockdown of GAS5 causes tamoxifen resistance and reduces the chemotherapeutic effect of dendrosomal curcumin in breast cancer cells. 10 Intriguingly, our finding substantiated that elevation of GAS5 antagonized the activation of autophagy in cisplatin-exposed cells. 23 Further mechanism analysis conferred that exposure to cisplatin evoked excessive autophagy by increasing the conversion of LC3I to LC3II and suppressing p62 accumulation, both markers to evaluate autophagic flux.…”

“…9 Analogously, targeting endoplasmic reticulum stress-mediated autophagy elevates the effectiveness of sunitinib and gemcitabine on pancreatic cancer. 10 However, several lines of research have confirmed the protective roles of autophagy in glioma cell growth during chemotherapy. 8 Similarly, overexpression of miR-519a promotes autophagy in glioblastoma and then sensitizes the cell to chemotherapy.…”

Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

“…The role of autophagy in GBM cells in response to metabolic and therapeutic stress seems to be different, including prosurvival and prodeath (22). Moreover, accumulating evidence has revealed a positive correlation between chemoresistance and autophagy reduction in GBM cells (23,24).…”

RETRACTED ARTICLE: Flot2 targeted by miR-449 acts as a prognostic biomarker in glioma

“…For example, miR-200a, an anti-Galphai1 miRNA, downregulation in human glioma and involved cell proliferation of glioma [17]. miR-519a, as a tumour suppressor, promotes autophagy in glioma [18]. miR-181a was reported to reduce cell proliferation and invasion in glioma [19].…”