Abstract
Glioma is the most common type of malignant tumor of the nervous system and is characterized by high mortality and poor outcome. This study aims to investigate the mechanism underlying IGF2 mRNA-binding protein 2 (IGF2BP2) and long noncoding RNA DANCR in etoposide resistance of glioblastoma (GBM) cells. Bioinformatics analysis identified the IGF2BP2-related regulators and DANCR target genes, which were subsequently evaluated by RNA pull-down and RIP assays. We exposed GBM cells to etoposide and thus established etoposide-resistant cells. Through functional experiments, we evaluated the interrelationship among IGF2BP2, DANCR, phosphotyrosine interaction domain containing 1 (PID1), and forkhead box protein O1 (FOXO1) and further assessed their impact on the sensitivity of GBM cells to etoposide. IGF2BP2 and DANCR were highly expressed in glioma cells and tissues, whereas PID1 and FOXO1 were poorly expressed. Mechanistically, overexpression of IGF2BP2 promoted DANCR stability and reduced DANCR methylation, whereas silencing of IGF2BP2 reduced survival of GBM cells and etoposide-resistant cells. Besides, DANCR interacted with FOXO1 to promote the ubiquitination of FOXO1. FOXO1 promoted the transcriptional expression of PID1, enhancing the chemotherapy sensitivity of GBM cells, but overexpression of PID1 reversed the impact of IGF2BP2. Collectively, IGF2BP2 inhibits PID1 expression through the DANCR/FOXO1 axis, inducing drug resistance in GBM cells, and promoting glioma progression.
Highlights
Brain tumors are commonly occurring solid tumors that cause significant cancer-related mortality (McNeill, 2016)
We checked the expression of IGF2 mRNA-binding protein 2 (IGF2BP2) in various GBM cell lines (U251, LN229, LN18, and T98G), all of which presented with higher IGF2BP2 expression level relative to primary normal human astrocytes (NHA) (Figures 1E,F)
Combined treatment of IGF2BP2 + phosphotyrosine interaction domain containing 1 (PID1) or DANCR + PID1 elevated Ki67 protein expression, but diminished the survival rate of nude mice (Supplementary Figures S4A–C; Supplementary Table S3). These lines of evidence indicated that IGF2BP2 promoted etoposide resistance in GBM cells through the DANCR/ PID1 axis
Summary
Brain tumors are commonly occurring solid tumors that cause significant cancer-related mortality (McNeill, 2016). With the exception of temozolomide, GBM is relatively unresponsive to IGF2BP2 Induces Glioblastoma Cell Chemoresistance most chemotherapy agents (Tan et al, 2020). It is imperative to clarify the mechanisms of resistance to etoposide, aiming to develop an improved chemotherapy for glioma. Apart from drug resistance, the blood–tumor barrier (BTB) is characterized by numerous distinct features, which can significantly attenuate the efficacy of chemotherapy for glioma (Arvanitis et al, 2020). Knockdown of IGF2 mRNA-binding protein 2 (IGF2BP2) is noted to decrease the expression of long noncoding RNAs (lncRNAs) and tight junction–related proteins, thereby promoting BTB permeability in glioma and enhancing antitumor efficacy of certain drugs (Liu et al, 2020). The mechanism underlying the role of IGF2BP2 in glioma resistance remains elusive, and its association with lncRNAs merits further attention
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