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Microarray Expression Profiles and bioinformatics analysis of mRNAs, lncRNAs and circRNAs in the secondary temozolomide-resistant glioblastoma

ABSTRACT: Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumor. Although comprehensive therapies combining radiotherapy and chemotherapy after surgery can prolong survival, the prognosis is still poor with a median survival of only 14.6 months. Chemoresistance is one of the major causes of relapse as well as poor survival in glioma patients. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Recent studies have demonstrated that long non‑coding RNAs are closely related to resistance to cancer chemotherapy. Here, we simultaneously detected, for the ﬁrst time, the expression proﬁles of mRNAs, lncRNAs, and circRNAs in three pairs of secondary temozolomide-resistant glioblastoma (STRG) and matched primary glioblastoma tissues by microarrays. A total of 92 mRNA, 299lncRNAs, and 53 circRNAs were altered during the Chemoresistance. The functions of these differentially expressed RNAs were predicted by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Co-expression networks of lncRNA-mRNA and circRNA-miRNA were conducted to uncovered the hidden ceRNA mechanisms. Our findings revealed the alteration of expression patterns of mRNAs, lncRNAs, and circRNAs in the secondary temozolomide-resistant glioblastoma. These mRNAs, lncRNAs, and circRNAs might be potential therapeutic targets for the treatment of glioblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139826 | GEO | 2020/12/17

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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Microarray Expression Profiles and bioinformatics analysis of mRNAs, lncRNAs and circRNAs in the secondary temozolomide-resistant glioblastoma

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