Abstract
Temozolomide (TMZ) and radiation therapy combination for glioblastoma (GB) patients has been considered as the most effective therapy after surgical procedure. However, the overall clinical prognosis remains unsatisfactory due to intrinsic or developing resistance to TMZ. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in TMZ resistance is poorly understood. Here, we found that the expression of lncRNA AC003092.1 was markedly decreased in TMZ resistance (TR) of GB cells (U87TR and U251TR) compared with their parental cells (U87 and U251). In patients with glioma, low levels of lncRNA AC003092.1 were correlated with increased TMZ resistance, higher risk of relapse, and poor prognosis. Overexpression of lncRNA AC003092.1 enhances TMZ sensitivity, facilitates cell apoptosis, and inhibits cell proliferation in TMZ-resistant GB cells. In addition, we identified that lncRNA AC003092.1 regulates TMZ chemosensitivity through TFPI-2-mediated cell apoptosis in vitro and in vivo. Mechanistically, further investigation revealed that lncRNA AC003092.1 regulates TFPI-2 expression through miR-195 in GB. Taken together, these data suggest that lncRNA AC003092.1 could inhibit the function of miR-195 by acting as an endogenous CeRNA, leading to increased expression of TFPI-2; this promotes TMZ-induced apoptosis, thereby making GB cells more sensitive to TMZ. Our findings indicate that overexpression of lncRNA AC003092.1 may be a potential therapy to overcome TMZ resistance in GB patients.
Highlights
Glioblastoma (GB) is one of the most aggressive primary brain tumors in adults with widespread invasion and resistance to traditional treatments[1,2]
Among the differentially expressed long noncoding RNAs (lncRNAs), we found that the lncRNA AC003092.1 with 639nucleotide length, known as ENST00000415536, was mostly downregulated with 43.99-fold, while its nearby gene TFPI-2 was downregulated with 607.05-fold change within U87TR cells, as compared with its parental U87 cells (Fig. 1a)
Through CCK8 assay, we found that lncRNA AC003092.1 overexpression significantly decreased the cell viability in U87TR and U251TR cells with relatively lower IC50 values, as compared to the V-NC groups treated with 50 μg/ml TMZ for 48 h (Fig. 2a, b)
Summary
Glioblastoma (GB) is one of the most aggressive primary brain tumors in adults with widespread invasion and resistance to traditional treatments[1,2]. MGMT removes cytotoxic lesions generated by TMZ, and its promoter methylation is correlated with improved overall survival and reduced progression in patients treated with TMZ8–11. Xu et al Cell Death and Disease (2018)9:1139 methylation respond to TMZ, indicating that MGMT is not the only factor contributing to TMZ resistance. Elucidation of molecular mechanisms underlying TMZ resistance could provide potential novel targets for GB treatments. Several lines of evidence point to the functional role of dysregulated lncRNA in the cancer formation and progression, as well as the resistance to chemotherapy[15,16]. Our microarray analysis showed 2,692 lncRNAs and 2,933 mRNAs exhibiting a change of more than 2.0-fold in TMZ-resistant U87 (U87TR) cells[20]. Far less is known about the role of lncRNA AC003092.1-mediated regulation of TMZ resistance in GB as well as the underlying mechanism
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