Abstract
Gliomas are the most fatal malignant cerebral tumors. Temozolomide (TMZ), as the primary chemotherapy drug, has been widely used in clinics. However, resistance of TMZ still remains to poor defined. LncRNAs have been reported to play crucial roles in progression of various cancers and resistance of multiple drugs. However, the biological function and underlying mechanisms of most lncRNAs in glioma still remains unclear. Based on the TCGA database, a total of 94 differentially expressed lncRNAs, including 16 up-regulated genes and 78 downregulated genes were identified between gliomas and normal brain tissues. Subsequently, lncRNA DLEU1, HOTAIR, and LOC00132111 were tested to be significantly related to overall survival (OS) between high- and low-expression groups. Additionally, we verified that lncRNA DLEU1 was high expressed in 108 gliomas, compared with 19 normal brain tissues. And high expression of lncRNA DLEU1 predicted a poor prognosis (HR = 1.703, 95%CI: 1.133–2.917, p-value = 0.0159). Moreover, functional assays revealed that knockdown of lncRNA DLEU1 could suppress the proliferation by inducing cell cycle arrest at G1 phase and reducing the S phase by down-regulating the CyclinD1 and p-AKT, as the well as migration and invasion by inhibiting the epithelial–mesenchymal transition (EMT) markers, such as ZEB1, N-cadherin, β-catenin and snail in glioma cells. Furthermore, silencing lncRNA DLEU1 suppressed TMZ-activated autophagy via regulating the expression of P62 and LC3, and promoted sensitivity of glioma cells to TMZ by triggering apoptosis. Conclusively, our study indicated that lncRNA DLEU1 might perform as a prognostic potential target and underlying therapeutic target for sensitivity of glioma to TMZ.
Highlights
Glioma, accounting for approximately 80% of malignant tumors, is one of the most primary and fatal intracranial tumors (Jin et al, 2019; Wu et al, 2019)
Based on RNA-seq data from The Cancer Genome Atlas (TCGA), we demonstrated that the differential expression gene in glioma, named lncRNA deleted in lymphocytic leukemia 1, was dramatically associated with a poor prognosis
We revealed the underlying mechanism of lncRNA DLEU1 involved in sensitivity of glioma cells to TMZ, which provided a potential target for the individualized therapy of temozolomide in glioma
Summary
Glioma, accounting for approximately 80% of malignant tumors, is one of the most primary and fatal intracranial tumors (Jin et al, 2019; Wu et al, 2019). Despite advances in diagnosis and therapy such as surgical resection followed by adjuvant radiotherapy and chemotherapy, patients with glioblastoma have a median survival time of merely 12–15 months Parsons et al, 2008; Mostafa et al, 2016). Temozolomide (TMZ), the primary chemotherapeutic drug for gliomas, was reported to prolong the survival time of glioblastoma patients (Nanegrungsunk et al, 2015; Wait et al, 2015). Several biomarkers such as MGMT, STAT3, and APNG have been explored to be associated with the sensitivity of TMZ (Jacinto and Esteller, 2007; Agnihotri et al, 2012; Lee et al, 2011), TMZ resistance in gliomas is still incompletely elaborated. The research for novel chemotherapeutic targets is crucial for glioma therapy
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