Abstract
Long non-coding RNAs (lncRNAs) have been widely reported to regulate the development and chemoresistance of a variety of tumors. Temozolomide (TMZ) is a first-line chemotherapy for treatment of glioma. However, the effect and the regulatory mechanism of lncRNA MSC-AS1 (MSC-AS1) in TMZ-resistant glioma remain unrevealed. Levels of MSC-AS1, microRNA-373-3p (miR-373-3p), and cytoplasmic polyadenylation element binding protein 4 (CPEB4) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). All protein expression was detected by western blot. Cell viability and the half maximal inhibitory concentration (IC50) value of TMZ was assessed by cell counting kit-8 (CCK-8) assay. Cell cloning ability and apoptosis were examined by colony formation and flow cytometry assays, respectively. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the correlation between miR-373-3p and MSC-AS1 or CPEB4. The xenograft models were established to determine the effect of MSC-AS1 in vivo. MSC-AS1 was up-regulated in TMZ-resistant glioma tissues and cells, and glioma patients with high MSC-AS1 expression tend to have lower overall survival rate. MSC-AS1 suppression reduced the IC50 value of TMZ and proliferation, promoted apoptosis and TMZ sensitivity, and affected PI3K/Akt pathway in TMZ-resistant glioma cells. MSC-AS1 acted as miR-373-3p sponge, and miR-373-3p directly targeted CPEB4. Silencing miR-373-3p reversed the promoting effect of MSC-AS1 or CPEB4 knockdown on TMZ sensitivity. Furthermore, MSC-AS1 knockdown inhibited TMZ-resistant glioma growth in vivo by regulating miR-373-3p/CPEB4 axis through PI3K/Akt pathway. Collectively, MSC-AS1 knockdown suppressed cell growth and the chemoresistance of glioma cells to TMZ by regulating miR-373-3p/CPEB4 axis in vitro and in vivo through activating PI3K/Akt pathway.
Highlights
Glioma is one of the most common malignant brain tumors, accounting for 40–50% of intracranial tumors [1]
Many reports have revealed the role of cytoplasmic polyadenylation element binding protein 4 (CPEB4) in glioma, as it was upregulated in glioma, and it could be regulated by the long noncoding RNAs (lncRNAs) FOXD2-AS1/miR-98-5p axis to participate in glioma cell proliferation, metastasis, and TMZ resistance [21]
Since MSC-AS1 could act as miR-373-3p sponge, and CPEB4 was the target for miR-373-3p, we further explored whether MSC-AS1 could regulate CPEB4 expression by targeting miR-373-3p
Summary
Glioma is one of the most common malignant brain tumors, accounting for 40–50% of intracranial tumors [1]. LncRNA CASC2 restrained the growth and TMZ resistance of glioma cells by sponging miR-181a [10]. LncRNA XIST could enhance the resistance of glioma cells to TMZ through interacting. The expression pattern and mechanism of MSC-AS1 in glioma remain unknown, let alone the regulation of TMZ resistance. We wondered whether miR-373-3p could modulate the TMZ resistance in glioma cells. Many reports have revealed the role of CPEB4 in glioma, as it was upregulated in glioma, and it could be regulated by the lncRNA FOXD2-AS1/miR-98-5p axis to participate in glioma cell proliferation, metastasis, and TMZ resistance [21]. Whether there was a link between miR-373-3p and CPEB4 in TMZ-resistant glioma remains unclear. Whether MSC-AS1 activates the PI3K/AKT signaling pathway in TMZ-resistant glioma remains to be further elaborated. The established TMZ-resistant cells were named as LN229/TR and SHG-44/TR
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