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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Correlation between levels of clock protein expression and effects on temozolomide-resistant glioblastoma and tumor
Keng-Liang Kuo1,2, Shu-Jyuan Chang3,4, Aij-Lie Kwan1,5
1Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Abstract:
Glioblastoma (GBM) is the most common malignant intracranial neoplasm. Treatment with surgical resection and concurrent chemoradiotherapy may not achieve satisfactory results in life expectancy. Temozolomide (TMZ) chemoresistance is one of the most common reasons for treatment failure, but the role of the circadian cycle and autophagic pathways in this phenomenon is unknown. This study investigated the relationship between the circadian cycle and autophagic pathways in GBM and its TMZ chemoresistance counterpart. The predictive potential of NR1D1 and MGMT was analyzed by using 631 glioma cases derived from the TCGA GBM dataset. Human GBM cell lines (U-87 MG, GBM 8401) and their TMZ chemoresistance counterparts were used for MGMT, circadian proteins (CLOCK, BMAL1, NR1D1), and LC3B analysis. In addition, immunohistochemical staining for NR1D1 was performed in 78 GBM samples, and the results were analyzed with patients' clinicopathological parameters. Results revealed a decrease in NR1D1 expression in GBM cells which could enhance TMZ chemosensitivity. Different expressions of autophagic markers were also noted in GBM cell lines with and without TMZ chemoresistance, indicating a significant role for NR1D1 in TMZ chemoresistance in the GBM cell line. In addition, higher expression of NR1D1 in tumor samples was correlated with poor prognosis and shorter survival. In conclusion, high levels of NR1D1 not only could predict poor prognosis but it could also be used as a chemosensitizer for TMZ in GBM patients.
Insights
High NR1D1 levels in glioblastoma (GBM) predict poor prognosis and shorter survival. Targeting NR1D1 may enhance temozolomide (TMZ) chemosensitivity, offering a potential therapeutic strategy for GBM patients.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Chronobiology
Background:
- Glioblastoma (GBM) is a primary brain tumor with poor prognosis.
- Temozolomide (TMZ) resistance is a major challenge in GBM treatment.
- The roles of circadian rhythms and autophagy in TMZ resistance are unclear.
Purpose of the Study:
- To investigate the link between circadian cycle, autophagy, and TMZ chemoresistance in GBM.
- To evaluate NR1D1 as a predictive marker for GBM prognosis and TMZ response.
Main Methods:
- Analysis of 631 TCGA GBM cases for NR1D1 and MGMT predictive potential.
- Assessment of MGMT, circadian proteins (CLOCK, BMAL1, NR1D1), and LC3B in human GBM cell lines and TMZ-resistant counterparts.
- Immunohistochemical staining for NR1D1 in 78 GBM samples, correlated with clinicopathological data.
Main Results:
- Decreased NR1D1 expression in GBM cells correlated with enhanced TMZ chemosensitivity.
- Differential expression of autophagy markers observed in TMZ-resistant vs. sensitive GBM cells.
- Higher NR1D1 expression in tumor samples associated with poor prognosis and reduced survival.
Conclusions:
- NR1D1 plays a significant role in TMZ chemoresistance in GBM.
- Elevated NR1D1 levels predict poor prognosis in GBM patients.
- NR1D1 could serve as a potential chemosensitizer to improve TMZ efficacy in GBM.
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