Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited therapeutic options. Temozolomide (TMZ) is a novel cytotoxic agent used as first-line chemotherapy for GBM, however, some individual cells can't be isolated for surgical resection and show treatment-resistance, thus inducing poor prognosis. By using the HiSeq sequencing and bioinformatics methods, we identified lncRNAs showing different expression levels in TMZ-resistant and non-resistant patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MALAT1 was finally identified to show considerable discriminating potential to identify responding patients from non-responding patients. Moreover, high serum MALAT1 expression was associated with poor chemoresponse and survival in GBM patients receiving TMZ treatment. Subsequently, the TMZ resistant cell lines were established, and the CCK8 assay showed that lncRNA MALAT1 knockdown significantly reversed TMZ resistance in GBM cells. The gain and loss-function experiments revealed that miR-203 was down-regulated by MALAT1 and this interaction has reciprocal effects. Besides, thymidylate synthase (TS) mRNA was identified as a direct target of miR-203. LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR-203 and down-regulating TS expression. On the other hand, MALAT1 overexpression promoted resistance by suppressing miR-203 and promoting TS expression. In conclusion, our integrated approach demonstrates that enhanced expression of lncRNA MALAT1 confers a potent poor therapeutic efficacy and inhibition of MALAT1 levels could be a future direction to develop a novel therapeutic strategy to overcome TMZ resistance in GBM patients.
Highlights
Glioblastoma multiforme (GBM) is one of the most common and aggressive form of primary brain tumors
The Hiseq sequencing with six tissue samples pooled from GBM patient showing response and six from patients showing no response to TMZ treatment were conducted
The chosen Long noncoding RNAs (lncRNAs) were subjected to reverse transcription quantitative real-time PCR (RT-qPCR) assay to validate the deregulation
Summary
Glioblastoma multiforme (GBM) is one of the most common and aggressive form of primary brain tumors. It represents 12–15% of intracranial tumors and. Temozolomide (TMZ)based chemotherapy after surgical resection is one of the www.impactjournals.com/oncotarget most frequently used therapeutic strategies. A large proportion of patients receiving chemotherapy become metastatic and chemoresistant, and this has been a key barrier to the efficacy of GBM treatment [4]. Previous study indicated that more than half of the patients were detected with overexpression of O-6methylguanine-DNA methyltransferase (MGMT), which further leads to the failure of TMZ-based treatment [5].
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