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Updated: Jul 30, 2025
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression
Jen-Tsung Yang1,2, I-Neng Lee3, Cheng Huang4
1Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan.
Abstract:
Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
Insights
Glioblastoma resistance to temozolomide (TMZ) can be overcome by targeting ADAM17. Inhibiting ADAM17 with miR-145 enhances TMZ sensitivity in glioblastoma, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor often treated with temozolomide (TMZ).
- The role of A disintegrin and metalloproteinases (ADAMs) in modulating TMZ sensitivity in GBM remains largely unknown.
- ADAM17 is a potential target due to its observed upregulation in GBM.
Purpose of the Study:
- To investigate the role of ADAM17 in temozolomide (TMZ) resistance in glioblastoma (GBM).
- To explore the potential of microRNAs (miRNAs) in regulating ADAM17 and TMZ sensitivity.
- To analyze the clinical relevance of ADAM17 and specific miRNAs in GBM prognosis.
Main Methods:
- RNA sequencing to identify ADAM expression changes upon TMZ treatment.
- Establishment of TMZ-resistant GBM cell lines for functional studies.
- In vitro and in vivo experiments involving ADAM17 knockdown and miRNA mimic transfection.
- Analysis of clinical GBM specimens for ADAM17 and miRNA expression correlation with prognosis.
Main Results:
- ADAM17 expression was significantly upregulated in GBM cells under TMZ treatment and in TMZ-resistant cell lines.
- Knockdown of ADAM17 enhanced TMZ sensitivity in both in vitro and in vivo GBM models.
- Overexpression of miR-145 suppressed ADAM17 expression and increased TMZ sensitivity.
- Clinical GBM samples showed elevated ADAM17 and decreased miR-145 levels, correlating with disease progression and poor prognosis.
Conclusions:
- ADAM17 plays a crucial role in mediating TMZ resistance in glioblastoma.
- miR-145 enhances TMZ sensitivity by directly inhibiting ADAM17 expression.
- Targeting the miR-145/ADAM17 axis presents a promising therapeutic strategy for overcoming TMZ resistance in GBM.
