Roth Sarah Andrea, Knutsen Erik, Fiskaa Tonje, Utnes Peter, Bhavsar Swapnil, Hald Øyvind H, Løkke Cecilie, Mestdagh Pieter, Johansen Steinar D, Flægstad Trond, Einvik Christer
Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway.
RNA and Molecular Pathology (RAMP), Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway.
Cancer Lett. 2016 Mar 1;372(1):128-36. doi: 10.1016/j.canlet.2015.11.026. Epub 2015 Dec 17.
Neuroblastoma is a pediatric cancer of the developing sympathetic nervous system. High risk neuroblastoma patients typically undergo an initial remission in response to treatment, followed by recurrence of aggressive tumors that have become refractory to further treatment. Recent works have underlined the involvement of microRNAs (miRNAs) in neuroblastoma development and evolution of drug resistance. In this study we have used deep sequencing technology to identify miRNAs differentially expressed in neuroblastoma cell lines isolated from 6 patients at diagnosis and at relapse after intensive treatments. This approach revealed a panel of 42 differentially expressed miRNAs, 8 of which were upregulated and 34 were downregulated. Most strikingly, the 14q32 miRNA clusters encode 22 of the downregulated miRNAs. Reduced expression of 14q32 miRNAs in tumors associated with poor prognosis factors was confirmed in a cohort consisting of 226 primary neuroblastomas. In order to gain insight into the nature of the genes that may be affected by the differentially expressed miRNAs we utilized Ingenuity Pathway Analysis (IPA). This analysis revealed several biological functions and canonical pathways associated with cancer progression and drug resistance. The results of this study contribute to the identification of miRNAs involved in the complex processes of surviving therapeutic treatment and developing drug resistance in neuroblastoma.
神经母细胞瘤是一种发生于发育中的交感神经系统的儿科癌症。高危神经母细胞瘤患者通常在接受治疗后会出现初始缓解，但随后会复发侵袭性肿瘤，这些肿瘤对进一步治疗产生耐药性。最近的研究强调了微小RNA（miRNA）在神经母细胞瘤发展和耐药性演变中的作用。在本研究中，我们使用深度测序技术来鉴定在6例患者诊断时及强化治疗后复发时分离的神经母细胞瘤细胞系中差异表达的miRNA。该方法揭示了一组42个差异表达的miRNA，其中8个上调，34个下调。最显著的是，14q32 miRNA簇编码了22个下调的miRNA。在一个由226例原发性神经母细胞瘤组成的队列中，证实了与不良预后因素相关的肿瘤中14q32 miRNA表达降低。为了深入了解可能受差异表达的miRNA影响的基因的性质，我们利用了 Ingenuity Pathway Analysis（IPA）。该分析揭示了与癌症进展和耐药性相关的几种生物学功能和经典途径。本研究结果有助于鉴定参与神经母细胞瘤治疗存活和产生耐药性复杂过程的miRNA。
