Abstract
Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.
Highlights
Glioma is the commonest brain and central nervous system malignant tumor, accounting for approximately 80% of all malignant intracranial tumor cases [1]
Effects of RNA component of mitochondrial RNA processing endoribonuclease (RMRP) knockdown on glioma cell proliferation, apoptosis, and TMZ resistance To have a deep insight into the functions of RMRP in glioma samples
We demonstrated that RMRP depletion reduced the resistance of glioma cells to TMZ in vitro and inhibited the growth of TMZ-treated glioma xenograft tumors in vivo
Summary
Glioma is the commonest brain and central nervous system malignant tumor, accounting for approximately 80% of all malignant intracranial tumor cases [1]. More than 50% of glioma cases are diagnosed at the late stage (WHO grade IV glioblastoma), while glioblastoma patients after routine treatment have a poor prognosis with a 5-year survival rate of less than 5% [1, 2]. Temozolomide (TMZ), an orally bioavailable DNA alkylating agent, has been a backbone of glioma treatment for more than 20 years due to its ability to penetrate the blood-brain barrier [8, 9]. TMZ only can slightly increase the survival of patients with glioblastoma and many patients with glioblastoma have poor or no responses to TMZ, which is mainly caused by inherent and acquired TMZ resistance [10, 11]. It is imperative to clarify the molecular mechanisms of TMZ resistance and identify novel targets to improve its therapeutic efficacy
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