Glioblastoma (GBM) is the most malignant subtype of gliomas. GBM resistance to temozolomide (TMZ) remains a huge challenge. O6-methylguanine-DNA methyltransferase (MGMT) is mainly responsible for repairing DNA alkylation damage caused by alkylating drugs such as TMZ; therefore, it has been regarded as the major cause of the resistance to TMZ. Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were performed in tissue sections. LncRNA urothelial cancer-associated 1 (UCA1) knockdown was conducted via the transfection of the plasmid containing small interfering RNA (siRNA) targeting lncRNA UCA1. Cell viability and apoptosis were examined using MTT assay and flow cytometry. Nude mouse tumorigenicity assay was performed to detect tumor formation in vivo. MGMT expression and lncRNA UCA1 expression were increased in high-grade glioma tissues and cells. UCA1 knockdown in glioma cells enhanced TMZ efficacies in affecting glioma cell viability, cell apoptosis, MGMT protein level, and DNA damage markers in vitro, as well as tumorigenesis in vivo. Moreover, miR-182-5p targeted UCA1 and MGMT; miR-182-5p inhibited MGMT expression. Similar to UCA1 knockdown, miR-182-5p overexpression also promoted TMZ effects on glioma cell phenotype, MGMT expression level, and the levels of DNA damage markers. Under TMZ treatment, the efficacies of UCA1 knockdown in MGMT expression level and glioma cell sensitivity to TMZ were notably reversed after miR-182-5p overexpression. Taken together, we demonstrate the lncRNA UCA1/miR-182-5p/MGMT axis modulates glioma cell sensitivity to TMZ via MGMT-related DNA damage pathways.
Keywords: Glioblastoma (GBM); LncRNA UCA1; MGMT; Temozolomide (TMZ); miR-182-5p.
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