当前位置: X-MOL 学术Neoplasia › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Irreversible and sustained upregulation of endothelin axis during oncogene-associated pancreatic inflammation and cancer.
Neoplasia ( IF 6.3 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.neo.2019.11.001
Suprit Gupta 1 , Avi Prajapati 1 , Mansi Gulati 1 , Shailendra K Gautam 1 , Sushil Kumar 1 , Vipin Dalal 1 , Geoffrey A Talmon 2 , Satyanarayana Rachagani 1 , Maneesh Jain 3
Affiliation  

Endothelin-1 (ET-1) and its two receptors, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) exhibit deregulated overexprerssion in pancreatic ductal adenocarcinoma (PDAC) and pancreatitis. We examined the expression pattern of endothelin (ET) axis components in the murine models of chronic and acute inflammation in the presence or absence of oncogenic K-ras. While the expression of endothelin converting enzyme-1 (ECE-1), ET-1, ETAR and ETBR in the normal pancreas is restricted predominantly to the islet cells, progressive increase of ET receptors in ductal cells and stromal compartment is observed in the KC model (Pdx-1 Cre; K-rasG12D) of PDAC. In the murine pancreas harboring K-rasG12D mutation (KC mice), following acute inflammation induced by cerulein, increased ETAR and ETBR expression is observed in the amylase and CK19 double positive cells that represent cells undergoing pancreatic acinar to ductal metaplasia (ADM). As compared to the wild type (WT) mice, cerulein treatment in KC mice resulted in significantly higher levels of ECE-1, ET-1, ETAR and ETBR, transcripts in the pancreas. Similarly, in response to cigarette smoke-induced chronic inflammation, the expression of ET axis components is significantly upregulated in the pancreas of KC mice as compared to the WT mice. In addition to the expression in the precursor pancreatic intraepithelial neoplasm (PanIN lesions) in cigarette smoke-exposure model and metaplastic ducts in cerulein-treatment model, ETAR and ETBR expression is also observed in infiltrating F4/80 positive macrophages and α-SMA positive fibroblasts and high co-localization was seen in the presence of oncogenic K-ras. In conclusion, both chronic and acute pancreatic inflammation in the presence of oncogenic K-ras contribute to sustained upregulation of ET axis components in the ductal and stromal cells suggesting a potential role of ET axis in the initiation and progression of PDAC.

中文翻译:


在癌基因相关的胰腺炎症和癌症过程中,内皮素轴不可逆且持续上调。



内皮素-1 (ET-1) 及其两种受体,内皮素受体 A (ETAR) 和内皮素受体 B (ETBR) 在胰腺导管腺癌 (PDAC) 和胰腺炎中表现出过度表达失调。我们检查了存在或不存在致癌 K-ras 的慢性和急性炎症小鼠模型中内皮素 (ET) 轴成分的表达模式。虽然正常胰腺中内皮素转换酶-1 (ECE-1)、ET-1、ETAR 和 ETBR 的表达主要限于胰岛细胞,但在 KC 中观察到导管细胞和基质室中 ET 受体的逐渐增加PDAC 模型(Pdx-1 Cre;K-rasG12D)。在携带 K-rasG12D 突变的小鼠胰腺(KC 小鼠)中,在雨蛙蛋白诱导的急性炎症后,在淀粉酶和 CK19 双阳性细胞中观察到 ETAR 和 ETBR 表达增加,这些细胞代表正在经历胰腺腺泡到导管化生 (ADM) 的细胞。与野生型 (WT) 小鼠相比,KC 小鼠中的雨蛙素治疗导致胰腺中 ECE-1、ET-1、ETAR 和 ETBR 转录物的水平显着升高。同样,为了应对香烟烟雾引起的慢性炎症,与 WT 小鼠相比,KC 小鼠胰腺中 ET 轴成分的表达显着上调。除了在香烟烟雾暴露模型中的前体胰腺上皮内肿瘤(PanIN 病变)和雨蛙素治疗模型中的化生导管中表达外,在浸润的 F4/80 阳性巨噬细胞和 α-SMA 阳性成纤维细胞中也观察到 ETAR 和 ETBR 表达在致癌 K-ras 存在的情况下观察到高度共定位。 总之,在致癌 K-ras 存在的情况下,慢性和急性胰腺炎症都会导致导管和基质细胞中 ET 轴成分的持续上调,表明 ET 轴在 PDAC 的启动和进展中具有潜在作用。
更新日期:2020-01-08
down
wechat
bug