Pulmonary Division, Department of Medicine, University of Helsinki, Helsinki, Finland.
Virchows Arch. 2014 Aug;465(2):173-83. doi: 10.1007/s00428-014-1602-x. Epub 2014 Jun 12.
Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.
神经内分泌肿瘤 (NET) 起源于弥散性神经内分泌细胞，并表达一般和特异性神经内分泌标志物。神经肽 S 受体 1 (NPSR1) 表达于神经内分泌细胞，其配体神经肽 S (NPS) 影响细胞增殖。我们的目的是研究 NPS/NPSR1 是否可作为神经内分泌肿瘤的生物标志物，并鉴定受 NPS/NPSR1 影响的基因通路。我们收集了一组由 91 个内分泌腺、消化道、皮肤和肺的 NET 样本组成的队列。通过免疫染色检测嗜铬粒蛋白 A 和突触素的表达来验证肿瘤类型，通过 Ki-67 增殖指数分析肿瘤分级。使用针对 NPS 的多克隆抗体和针对 NPSR1-A 氨基末端和羧基末端的单克隆抗体通过免疫组织化学定量 NPS 和 NPSR1 的表达。在过表达 NPSR1-A 的人 SH-SY5Y 神经母细胞瘤细胞系中研究了 NPS 对下游信号的影响，该细胞系具有神经内分泌起源。除了肾上腺嗜铬细胞瘤中 NPS/NPSR1 免疫反应性非常低外，NPSR1 和 NPS 在大多数 NET 组织中表达。NPSR1-A 过表达细胞的转录组分析显示，丝裂原活化蛋白激酶 (MAPK) 通路、昼夜活动、焦点黏附、转化生长因子β和细胞因子-细胞因子相互作用是 NPS 刺激后改变最明显的基因通路。我们的结果表明，NET 是 NPS 和 NPSR1 的来源，并且 NPS 影响与癌症相关的通路。
