Li Su-Chen, Shi Hao, Khan Mohid, Caplin Martyn, Meyer Tim, Öberg Kjell, Giandomenico Valeria
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.
Mol Cell Endocrinol. 2015 Sep 5;412:131-9. doi: 10.1016/j.mce.2015.06.003. Epub 2015 Jun 4.
This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETs) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LRP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control.
本研究旨在利用体外模型研究miR-196a的作用。在小肠神经内分泌肿瘤（SI-NETs）和肺神经内分泌肿瘤（NETs）中检测到了miR-196a。miR-196a靶标预测分析提示HOXA9、HOXB7、LRP4和RSPO2基因值得进一步研究。在不同疾病阶段的SI-NET组织标本以及未经治疗和接受生长抑素类似物治疗的肝转移患者的血清样本中均可检测到这四个基因的水平。使用miR-196a抑制剂来沉默其在NET细胞中的作用。我们发现，在沉默的NET细胞中，这四个靶基因在转录水平上显著上调。在miR-196a沉默的NET细胞中，HOXA9、HOXB7、LRP4和RSPO2编码的蛋白质在翻译水平上也上调。在miR-196a沉默的CNDT2.5和NCI-H727细胞中，miR-196a下游基因BMP4、ETS1、CTNNB1、FZD5、LRP5和LRP6在转录水平上显著上调。此外，miR-196a显然在NET细胞生长控制中不起作用。
