科研之友
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摘要
The acquisition of multidrug resistance is a major impediment to the successful treatment of neuroblastoma, a clinically heterogeneous cancer accounting for approximate to 15% of all pediatric cancer deaths. The MYCN transcription factor, whose gene is amplified in approximate to 30% of high-risk neuroblastoma cases, influences drug resistance by regulating a cadre of genes, including those involved with drug efflux, however, other high-risk subtypes of neuroblastoma lacking MYCN amplification, such as those with chromosome 11q deletions, also acquire multidrug resistance. To elucidate additional mechanisms involved with drug resistance in non-MYCN amplified tumour cells, an SK-N-AS subline (SK-N-AsCis24) that is significantly resistant to cisplatin and cross resistant to etoposide was developed through a pulse-selection process. High resolution aCGH analysis of SK-N-AsCis24 revealed a focal gain on chromosome 5 containing the coding sequence for the neural apoptosis inhibitory protein (NAIP). Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both SK-N-AsCis24 and in parental SK-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in SK-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting. Our findings provide biological novel insight into neuroblastoma drug-resistance and have implications for future therapeutic research. What's new? Just under one-third of high-risk neuroblastomas, in which drug resistance is a central feature, involve amplification of the MYCN gene. Resistance in remaining high-risk tumors may be determined by any of several non-MYCN amplification mechanisms. Here, analysis of an SK-N-AS subline (SK-N-AsCis24) lacking MYCN amplification but resistant to cisplatin and etoposide reveals a link between the development of drug resistance via apoptotic inhibition and the neural apoptosis inhibitory protein (NAIP) and its regulatory microRNA, miR-520f. NAIP upregulation was associated with DNA copy number gain on chromosome 5 and down-regulation of miRNA-520f. MiR-520f was discovered to be down-regulated post-chemotherapy.
- 出版日期2015-4-1
