AUTHOR=Li Dong-Mei , Chen Qiu-Dan , Wei Gui-Ning , Wei Jie , Yin Jian-Xing , He Jun-Hui , Ge Xin , Shi Zhu-Mei TITLE=Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6 JOURNAL=Frontiers in Oncology VOLUME=10 YEAR=2021 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.611699 DOI=10.3389/fonc.2020.611699 ISSN=2234-943X ABSTRACT=Purpose

Glioblastoma 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.

Methods

Quantitative 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.

Results

We 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.

Conclusions

These 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.