基因组分析鉴定出十二指肠和胰腺神经内分泌肿瘤转录靶标的差异。
Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours.
机构信息
Department of Medicine, University of Arizona Medical Center - University Campus, Tucson, Arizona, USA.
Department of Cellular and Molecular Medicine, University of Arizona Medical Center - University Campus, Tucson, Arizona, USA.
出版信息
BMJ Open Gastroenterol. 2021 Nov;8(1). doi: 10.1136/bmjgast-2021-000765.
OBJECTIVE
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups.
AIM
To identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumours.
DESIGN
Whole exome sequencing and RNA-sequencing were performed on surgically resected GEP-NETs (discovery cohort). RNA transcript profiles available in the Gene Expression Omnibus were analysed using R integrated software (validation cohort). Digital spatial profiling (DSP) was used to analyse paraffin-embedded GEP-NETs. Human duodenal organoids were treated with 5 or 10 ng/mL of tumor necrosis factor alpha (TNFα) prior to qPCR and western blot analysis of neuroendocrine cell specification genes.
RESULTS
Both the discovery and validation cohorts of small intestinal neuroendocrine tumours induced expression of mesenchymal and calcium signalling pathways coincident with a decrease in intestine-specific genes. In particular, calcium-related, smooth muscle and cytoskeletal genes increased in DGASTs, but did not correlate with mutation status. Interleukin 17 (IL-17) and tumor necrosis factor alpha (TNFα) signalling pathways were elevated in the DGAST RNA-sequencing. However, DSP analysis confirmed a paucity of immune cells in DGASTs compared with the adjacent tumour-associated Brunner's glands. Immunofluorescent analysis showed production of these proinflammatory cytokines and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) by the tumours and stroma. Human duodenal organoids treated with TNFα induced neuroendocrine tumour genes, , and .
CONCLUSIONS
Stromal-epithelial interactions induce proinflammatory cytokines that promote Brunner's gland reprogramming.
目的
胃肠胰神经内分泌肿瘤（GEP-NETs）涵盖了一组具有不同分泌产物和在胃肠道内位置的肿瘤。它们在美国所有成年人群中的患病率都在增加。
目的
使用全基因组分析来确定 GEP-NET 的可能来源，以区分小肠神经内分泌肿瘤，特别是十二指肠胃泌素瘤（DGAST），与胰腺神经内分泌肿瘤。
设计
对手术切除的 GEP-NET（发现队列）进行全外显子组测序和 RNA 测序。使用 R 集成软件分析基因表达综合数据库中可用的 RNA 转录谱（验证队列）。使用数字空间分析（DSP）分析石蜡包埋的 GEP-NET。用人十二指肠类器官在 qPCR 之前用 5 或 10ng/ml 肿瘤坏死因子-α（TNFα）处理，然后用 Western blot 分析神经内分泌细胞特化基因。
结果
小肠神经内分泌肿瘤的发现和验证队列均诱导了间充质和钙信号通路的表达，同时肠特异性基因减少。特别是，DGAST 中钙相关、平滑肌和细胞骨架基因增加，但与 突变状态无关。白细胞介素 17（IL-17）和肿瘤坏死因子-α（TNFα）信号通路在 DGAST 的 RNA 测序中升高。然而，DSP 分析证实与相邻肿瘤相关的 Brunner 腺相比，DGAST 中免疫细胞较少。免疫荧光分析显示这些促炎细胞因子和磷酸化信号转导和转录激活因子 3（pSTAT3）由肿瘤和基质产生。用 TNFα 处理的人十二指肠类器官诱导了神经内分泌肿瘤基因 、 、 和 。
结论
基质-上皮相互作用诱导促炎细胞因子，促进 Brunner 腺重编程。
Zotero 插件