Abstract
Resistance to temolozomide (TMZ), the standard chemotherapy agent for treating glioblastomas (GBM), is a major clinical problem for patients with GBM. Recently, long noncoding RNAs (lncRNAs) have been implicated in chemotherapy resistance in various cancers. In this study, we found that the level of the lncRNA RP11-838N2.4 was lower in TMZ-resistant GBM cells (U87TR, U251TR) compared to the parental, non-resistant GBM cells (U87, U251). In GBM patients, the decreased level of lncRNA RP11-838N2.4 correlated with higher risk of GBM relapse, as well as shorter postoperative survival times. We further found that lncRNA RP11-838N2.4 could enhances the cytotoxic effects of temozolomide to GBM cells both in vivo and in vitro. Moreover, lncRNA RP11-838N2.4 acts as an endogenous sponge, suppressing the function of miR-10a through conserved sequences and increasing the expression of EphA8 that enhanced the rate of cell apoptosis, thereby intensified sensitivity of GBM cells to TMZ. Additionally, lncRNA RP11-838N2.4 inhibited the activity of transforming growth factor-β (TGF-β) independent of miR-10a. Finally, Characterization of lncRNA RP11-838N2.4 could contribute to strategies for enhancing the efficacy of TMZ.
Highlights
Glioblastoma (GBM) is one of the most common malignant tumors in the central nervous system, with a median survival of 15 months after patient diagnosis [1]
To examine whether U87TR and U251TR were more resistant to TMZ than parent cells, U87 and U87TR, U251 and U251TR were cultured with TMZ 50μg/ml and CCK-8 was performed to assay cell viability
The results showed that U87TR and U251TR were more capable of growth than their parent cells, U87 and U251, when in cultured with TMZ (Figure 1B)
Summary
Glioblastoma (GBM) is one of the most common malignant tumors in the central nervous system, with a median survival of 15 months after patient diagnosis [1]. Some patients develop resistance to TMZ, and as such, the overall outcome of GBM patients has not exponentially improved [3]. Predicting the effectiveness of TMZ in patients with GBM and enhancing TMZ sensitivity are of paramount importance. Several studies have indicated that epigenetic modulation of O-6methylguanine DNA methyltransferase (MGMT) and mismatch repair (MMR) are mechanisms underlying TMZ resistance [2, 4]. The fact that reduced MGMT levels or stimulated MMR cannot completely prevent TMZ resistance, indicating there are other possible mechanisms that have yet to be elucidated [4, 5]
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