Abstract
PurposeGlioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.MethodsQuantitative reverse transcriptase-PCR (qRT-PCR), DNA methylation analysis, cell proliferation assay, flow cytometric analysis, invasion assay, in situ tumor formation experiment were performed to test the expression levels and functions of miR-137 in GBM. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry assay were used to identify and verify the target of miR-137.ResultsWe found that miR-137 was downregulated in primary and recurrent GBM compared with normal brain tissues. Overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ) by directly targeting low-density lipoprotein receptor-related protein 6 (LRP6) in GBM. Forced expression of LRP6 cDNA without its 3’-UTR region partly restored the effects of miR-137 in vitro and in vivo. Hypoxia-induced miR-137 methylation was responsible for the miR-137 suppression, leading to the cell chemoresistance and poor prognosis of GBM.ConclusionsThese findings demonstrated the detailed molecular mechanism of miR-137 in regulating GBM growth and chemoresistance in hypoxia microenvironment, suggesting the potentiality of miR-137 as a therapeutic target for GBM.
Highlights
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant tumor of the central nervous system (CNS), with a median survival of 14.6 months and a 5-year survival rate of only 5.5% [1]
We used Quantitative reverse transcriptase (qRT)-PCR to measure the expressions of miR-137 in clinical specimens (9 normal brain tissues and 59 GBM tissues) and determined that miR-137 were lower-expression in GBM tissue samples compared with normal brain tissues (Figure 1A)
In order to determine whether miR137 had function on GBM cell chemoresistance to TMZ, we firstly constructed two GBM cell lines that expressed miR-137 stably (Figure S1A), miR-137-overexpressing cells treated with TMZ were used to analyze cell viability and apoptosis
Summary
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant tumor of the central nervous system (CNS), with a median survival of 14.6 months and a 5-year survival rate of only 5.5% [1]. It is of great significance to elucidate the potential molecular mechanisms related to the promotion of chemotherapeutic resistance in GBM hypoxic microenvironment for the development of new treatment strategies. The aberrant expression of hypoxia-regulated miRNAs plays key roles in GBM development, including cell proliferation, apoptosis, and invasion as well as sensitize to TMZ in GBM therapy [6,7,8]. We found that the expressions of miR-26a and miR-137 in GBM cells after hypoxia treatment were significantly dysregulated, and hypoxia could induce the protective response to mitochondrion via HIF-1a-mediated miR-26a upregulation which was associated with TMZ resistance [5]. The mechanism of miR-137 regulating TMZ resistance under GBM hypoxic conditions has not been thoroughly elucidated
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