Abstract
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.
Highlights
In children with high-risk neuroblastoma (NBL), which represents the major cause of cancer-related deaths in infants, the overall five-year survival rate is approximately 40%.To date, there are no salvage treatment regimens known to be curative [1]
myocardial infarction associated transcript (MIAT) Expression Is Upregulated in Neuroblastoma Cell Lines and Tissues
We found a high MIAT expression in the NBL due to the microarray expression experiments in the NBL cell line
Summary
In children with high-risk neuroblastoma (NBL), which represents the major cause of cancer-related deaths in infants, the overall five-year survival rate is approximately 40%. NMYC amplification or overexpression is associated with increased energy metabolism, rapid tumor growth, short survival rates, and unfavorable histology [2]. It is a well-established poor prognostic marker for NBL and strongly correlates with higher tumor aggressiveness and treatment resistance [2,3,4]. LncRNAs contribute to various cellular processes in normal and disease states, and their expression is dysregulated in the majority of human cancers, including NBL [7]. Our results and findings reveal a connection between lncRNA MIAT and NMYC, as well as c-Myc and its potential in NBL tumorigenesis
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