Neuroblastoma (NBL) is the most common extracranial childhood malignant tumor and represents a major cause of cancer-related deaths in infants. NMYC amplification or overexpression is associated with the malignant behavior of NBL tumors. In the present study, we revealed an association between long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) and NMYC amplification in NBL cell lines and MIAT expression in NBL tissue samples. MIAT silencing induces cell death only in cells with NMYC amplification, but in NBL cells without NMYC amplification it decreases only the proliferation. MIAT downregulation markedly reduces the NMYC expression in NMYC-amplified NBL cell lines and c-Myc expression in NMYC non-amplified NBL cell lines, but the ectopic overexpression or downregulation of NMYC did not affect the expression of MIAT. Moreover, MIAT downregulation results in decreased ornithine decarboxylase 1 (ODC1), a known transcriptional target of MYC oncogenes, and decreases the glycolytic metabolism and respiratory function. These results indicate that MIAT is an upstream regulator of NMYC and that MIAT/NMYC axis disruption induces cell death in NMYC-amplified NBL cell lines. These findings reveal a novel mechanism for the regulation of NMYC in NBL, suggesting that MIAT might be a potential therapeutic target, especially for those with NMYC amplification.

• Keywords
• NMYC amplification, cell metabolism, lncRNA MIAT, neuroblastoma,
• MeSH
• Apoptosis MeSH
• Cell Cycle MeSH
• Glycolysis MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms metabolism   MeSH
• Neuroblastoma metabolism   MeSH
• Cell Movement MeSH
• Cell Proliferation MeSH
• N-Myc Proto-Oncogene Protein metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• RNA, Long Noncoding genetics   metabolism   MeSH
• Gene Expression Profiling MeSH
• Gene Silencing MeSH
• Cell Survival MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Miat long non-coding RNA MeSH Browser
• MYCN protein, human MeSH Browser
• N-Myc Proto-Oncogene Protein MeSH
• RNA, Long Noncoding MeSH

The efficiency of cisplatin (CDDP) is significantly hindered by the development of resistance during the treatment course. To gain a detailed understanding of the molecular mechanisms underlying the development of cisplatin resistance, we comparatively analyzed established a CDDP-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its susceptible parental cells (UKF-NB-4). We verified increased chemoresistance of UKF-NB-4CDDP cells by analyzing the viability, induction of apoptosis and clonal efficiency. To shed more light on this phenomenon, we employed custom cDNA microarray (containing 2234 probes) to perform parallel transcriptomic profiling of RNA and identified that 139 genes were significantly up-regulated due to CDDP chemoresistance. The analyses of molecular pathways indicated that the top up-regulation scoring functions were response to stress, abiotic stimulus, regulation of metabolic process, apoptotic processes, regulation of cell proliferation, DNA repair or regulation of catalytic activity, which was also evidenced by analysis of molecular functions revealing up-regulation of genes encoding several proteins with a wide-spectrum of enzymatic activities. Functional analysis using lysosomotropic agents chloroquine and bafilomycin A1 validated their potential to re-sensitize UKF-NB-4CDDP cells to CDDP. Taken together, the identification of alterations in specific genes and pathways that contribute to CDDP chemoresistance may potentially lead to a renewed interest in the development of novel rational therapeutics and prognostic biomarkers for the management of CDDP-resistant neuroblastoma.

• Keywords
• chemoresistance, cisplatin, lysosomes, microarray, neuroblastoma, transport,
• MeSH
• Clone Cells MeSH
• Drug Resistance, Neoplasm drug effects   genetics   MeSH
• Chloroquine pharmacology   MeSH
• Cisplatin pharmacology   therapeutic use   MeSH
• Gene Ontology MeSH
• Gene Regulatory Networks drug effects   MeSH
• Humans MeSH
• Lysosomes drug effects   metabolism   MeSH
• Macrolides pharmacology   MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma drug therapy   genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Transcriptome drug effects   genetics   MeSH
• Cell Shape drug effects   MeSH
• Up-Regulation drug effects   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• bafilomycin A1 MeSH Browser
• Chloroquine MeSH
• Cisplatin MeSH
• Macrolides MeSH