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Knockdown lncRNA DLEU1 Inhibits Gliomas Progression and Promotes Temozolomide Chemosensitivity by Regulating
Qiao-Li Lv1, Li-Chong Wang1,2, Dang-Chi Li3
1Jiangxi Key Laboratory of Translational Cancer Research, Department of Head and Neck Surgery, Jiangxi Cancer Hospital of Nanchang University, Nanchang, China.
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.
Insights
Long non-coding RNA DLEU1 promotes glioma progression and temozolomide resistance. Silencing DLEU1 inhibits proliferation, migration, and invasion, while enhancing sensitivity to temozolomide by affecting cell cycle and apoptosis.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Gliomas are aggressive brain tumors with limited treatment options.
- Temozolomide (TMZ) is a standard chemotherapy, but resistance remains a significant challenge.
- Long non-coding RNAs (lncRNAs) are implicated in cancer progression and drug resistance, but their roles in glioma are not fully understood.
Purpose of the Study:
- To identify differentially expressed lncRNAs in gliomas.
- To investigate the functional role of lncRNA DLEU1 in glioma progression and TMZ resistance.
- To explore the underlying molecular mechanisms of DLEU1 in glioma.
Main Methods:
- Analysis of TCGA database for differentially expressed lncRNAs.
- Correlation analysis between lncRNA expression and overall survival.
- Functional assays including cell proliferation, migration, invasion, cell cycle, apoptosis, and autophagy.
- Western blot analysis to assess protein expression levels.
Main Results:
- 94 differentially expressed lncRNAs were identified between gliomas and normal tissues.
- High expression of lncRNA DLEU1 was significantly associated with poor prognosis in glioma patients.
- Knockdown of DLEU1 suppressed proliferation, induced G1 cell cycle arrest, inhibited migration and invasion, reduced EMT markers, suppressed TMZ-induced autophagy, and promoted TMZ sensitivity by triggering apoptosis.
Conclusions:
- lncRNA DLEU1 is upregulated in gliomas and predicts poor prognosis.
- DLEU1 promotes glioma cell proliferation, migration, and invasion.
- DLEU1 confers resistance to temozolomide by regulating autophagy and apoptosis.
- lncRNA DLEU1 represents a potential prognostic and therapeutic target for glioma treatment.
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