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Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas
Xin Hui Derryn Chan1, Srikanth Nama, Felicia Gopal
1Institute of Medical Biology, Agency for Science Technology and Research, Singapore 138648, Singapore.
Abstract:
Malignant gliomas are the most aggressive forms of brain tumors, associated with high rates of morbidity and mortality. Recurrence and tumorigenesis are attributed to a subpopulation of tumor-initiating glioma stem cells (GSCs) that are intrinsically resistant to therapy. Initiation and progression of gliomas have been linked to alterations in microRNA expression. Here, we report the identification of microRNA-138 (miR-138) as a molecular signature of GSCs and demonstrate a vital role for miR-138 in promoting growth and survival of bona fide tumor-initiating cells with self-renewal potential. Sequence-specific functional inhibition of miR-138 prevents tumorsphere formation in vitro and impedes tumorigenesis in vivo. We delineate the components of the miR-138 regulatory network by loss-of-function analysis to identify specific regulators of apoptosis. Finally, the higher expression of miR-138 in GSCs compared to non-neoplastic tissue and association with tumor recurrence and survival highlights the clinical significance of miR-138 as a prognostic biomarker and a therapeutic target for treatment of malignant gliomas.
Insights
MicroRNA-138 (miR-138) is identified as a key driver in malignant glioma growth and survival. Inhibiting miR-138 halts tumor formation, suggesting its potential as a therapeutic target for brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant gliomas are aggressive brain tumors with poor outcomes.
- Glioma stem cells (GSCs) drive tumor recurrence and resistance to therapy.
- MicroRNA dysregulation is implicated in glioma initiation and progression.
Purpose of the Study:
- To identify microRNAs associated with GSCs.
- To investigate the role of microRNA-138 (miR-138) in GSC function and glioma tumorigenesis.
- To evaluate miR-138 as a potential therapeutic target and prognostic biomarker.
Main Methods:
- Identification of miR-138 as a molecular signature of GSCs.
- Functional inhibition of miR-138 using sequence-specific methods.
- In vitro studies assessing tumorsphere formation.
- In vivo studies evaluating tumorigenesis.
- Loss-of-function analysis to identify miR-138 regulatory network components impacting apoptosis.
Main Results:
- miR-138 is highly expressed in GSCs and promotes their growth and survival.
- Functional inhibition of miR-138 suppressed tumorsphere formation in vitro.
- Inhibition of miR-138 impeded tumor initiation and progression in vivo.
- The miR-138 regulatory network includes key regulators of apoptosis.
Conclusions:
- miR-138 is a critical regulator of GSC self-renewal and survival.
- miR-138 inhibition represents a promising therapeutic strategy for malignant gliomas.
- Elevated miR-138 levels in GSCs correlate with tumor recurrence and poor survival, establishing it as a prognostic biomarker.
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