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Updated: Dec 24, 2025
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
HOTAIR/miR-125 axis-mediated Hexokinase 2 expression promotes chemoresistance in human glioblastoma
Jinnan Zhang1,2, Guangyong Chen1,2, Yufei Gao1,2
1Department of Neurosurgery, The Third Hospital of Jilin University, Changchun, China.
Abstract:
Drug resistance is one of the major obstacles in glioblastoma (GBM) treatments using temozolomide (TMZ) based conventional chemotherapy. Recent studies revealed that Hexokinase 2 (HK2)-mediated glycolysis is one of the sources, as the association of chemoresistance and the expression of HK2 was confirmed in multiple cancers. However, there has been little knowledge of the functional contribution of HK2 to TMZ resistance in GBM. In our study, we found that HK2 expression is crucial for GBM proliferation and chemoresistance. In contrast to the healthy brain, HK2 expression is much higher in human GBM, especially in those patients with GBM recurrence. High HK2 expression is negatively related to the overall survival in GBM patients. HK2 depletion in GBM cells suppressed the GBM cell proliferation and increased sensitivity to TMZ-induced apoptosis. Both HK2-mediated glycolysis and mitochondria permeability transition pore opening (MPTP) were associated with its function in chemoresistance. Furthermore, we also revealed that the abnormal expression of HK2 was modulated by the expression of HOTAIR, a long non-coding RNA (lncRNA). The absence of HOTAIR in GBM cells suppressed the HK2 expression in protein and mRNA level and, therefore, inhibited the cell proliferation and enhanced the cytotoxicity of TMZ both in vivo and in vitro. HOTAIR promoted the expression of HK2 by targeting mir-125, which suppressed the GBM cell proliferation and increased the TMZ-induced apoptosis. These findings shed light on a new therapeutic strategy in modulating HOTAIR/miR-125, which may interfere with the expression of HK2, and enhance the therapeutic sensitivity of GBM to TMZ.
Insights
Hexokinase 2 (HK2) drives glioblastoma (GBM) growth and temozolomide (TMZ) resistance by promoting glycolysis. Targeting HOTAIR and miR-125 may overcome this resistance, offering a new therapeutic avenue for GBM patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Drug resistance, particularly to temozolomide (TMZ), is a significant challenge in glioblastoma (GBM) treatment.
- Hexokinase 2 (HK2)-mediated glycolysis has been implicated in chemoresistance across various cancers, but its specific role in GBM TMZ resistance is not well understood.
Purpose of the Study:
- To investigate the functional role of HK2 in GBM proliferation and TMZ chemoresistance.
- To elucidate the regulatory mechanism of HK2 expression in GBM, focusing on the involvement of long non-coding RNA HOTAIR and microRNA-125 (miR-125).
Main Methods:
- Analysis of HK2 expression in human GBM tissues and correlation with patient survival.
- In vitro and in vivo experiments involving HK2 depletion in GBM cells.
- Investigation of HOTAIR's effect on HK2 expression and GBM cell behavior.
- Exploration of the HOTAIR/miR-125/HK2 regulatory axis.
Main Results:
- HK2 expression is elevated in GBM, particularly in recurrent cases, and correlates with poor survival.
- HK2 depletion reduces GBM proliferation and enhances sensitivity to TMZ by affecting glycolysis and mitochondrial permeability.
- HOTAIR upregulates HK2 expression at both protein and mRNA levels, promoting GBM proliferation and TMZ resistance.
- HOTAIR targets miR-125 to increase HK2 expression, thereby inhibiting apoptosis and reducing TMZ efficacy.
Conclusions:
- HK2 plays a critical role in GBM proliferation and TMZ chemoresistance.
- The HOTAIR/miR-125 axis is a key regulator of HK2 expression in GBM.
- Modulating the HOTAIR/miR-125 pathway presents a potential therapeutic strategy to enhance TMZ sensitivity in GBM.
