Abstract
BackgroundThe regulatory roles of long non-coding RNA (lncRNA) CRNDE in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood. Therefore, the function, characteristics, and possible mechanism of CRNDE in TMZ-induced chemoresistance to GBM were explored.MethodsFirstly, the expression level of CRNDE in 58 cases of glioma tissue specimens and 30 cases of normal brain tissues were tested by qRT-PCR. Meanwhile, the correlation between CRNDE expression level, the clinicopathological characteristics, and survival time of patients with glioma were analyzed. Then, the CRNDE expression in various glioma cell lines was detected, and CRNDE knockdown cell models were constructed. Subsequently, to explore the effect of CRNDE on chemosensitivity to TMZ, cell viability was detected by the CCK-8 assay and IC50 values, and cell proliferation was detected by cell clone assay and EdU assay, as well as cell survival was detected by apoptosis with flow cytometry under TMZ treatment. Further, the expression of drug-resistance protein ABCG2, autophagy related proteins, and PI3K/Akt/mTOR pathway were measured by western blot or qRT-PCR in TMZ-treated glioma cells. Finally, the mouse tumor xenograft model was established and the tumor volume and weight were measured, and ABCG2 expression was conducted by immunohistochemistry assay.ResultsThe integrated results demonstrated lncRNA CRNDE was a poor prognosis factor for GBM patient, which was upregulated in patients who were resistant to TMZ, and closely associated with chemotherapeutic response status to TMZ treatment. Further, functional assays revealed that knockdown of CRNDE could notably reduce glioma cell viability and proliferation, and elevate cell apoptosis to enhance the chemosensitivity to TMZ in vitro and in vivo. Mechanistically, the depression of CRNDE could diminish the expression of LC3 II/I, Beclin1 and Atg5 and increase the p62 expression level to inhibit autophagy due to the activation of PI3K/Akt/mTOR pathway as well as highly correlated with ABCG2 expression.ConclusionsOverall, the study provided that lncRNA CRNDE is a reliable clinical predictor of outcome and prognosis and a potential biomarker for predicting TMZ treatment response in GBM by modulating the autophagy through PI3K/Akt/mTOR pathway and ABCG2 expression which may be a novel therapeutic target for regulating TMZ sensitivity to GBM.
Highlights
The regulatory roles of long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood
LncRNA CRNDE expression is upregulated in glioma and correlates with poor prognosis and TMZ resistance To analyze the expression of long non-coding RNA (lncRNA) CRNDE in glioma, the levels of CRDNE mRNA in 58 glioma specimens and 30 normal brain tissues were investigated by carrying out qRT-PCR
In conclusion, lncRNA CRNDE was associated with the malignant phenotypes of glioma and a poor prognosis for patients with GBM, which were firstly demonstrated in our integrated approach
Summary
The regulatory roles of long non-coding RNA (lncRNA) CRNDE in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood. Growing numbers of studies have focused on exploring the molecular modulatory network involved in investigating the effective therapeutic targets to overcome chemoresistance, it is still vital to elucidate the molecular mechanisms underlying and suppressing resistance to TMZ to provide and develop potential novel molecular targets for GBM therapy. Several studies have demonstrated that lncRNAs play a functional role in the dysregulation of resistance to TMZ in glioma through different mechanisms [11, 12]. The function and possible mechanism of CRNDE involved in the development of chemoresistance to TMZ in glioma, in GBM, remain unclear and have not yet been elucidated
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