ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation.
ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation.
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DOI：
10.1038/onc.2016.459
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发表时间：
2017-06-01
期刊：
影响因子：
8
通讯作者：
Crnogorac-Jurcevic T
中科院分区：
文献类型：
--
作者：
Dumartin L;Alrawashdeh W;Trabulo SM;Radon TP;Steiger K;Feakins RM;di Magliano MP;Heeschen C;Esposito I;Lemoine NR;Crnogorac-Jurcevic T
胰腺导管腺癌（PDAC）的发生机制尚不清楚。在本研究中，我们分析了前梯度-2（AGR 2）在胰腺肿瘤早期阶段的作用。慢性胰腺炎（CP）和PDAC组织中瘤周区域的免疫组化分析显示，AGR 2存在于管状复合体（TC）和早期胰腺上皮内瘤变（PanIN）中。此外，AGR 2也被发现在离散的亚群的非转化细胞邻近这些癌前病变。在来源于人患者来源的异种移植物（PDX）模型的原代细胞中，流式细胞术显示，与非干细胞癌细胞相比，AGR 2在胰腺癌干细胞（CSC）中过表达。在LSL-KrasG 12 D中; Pdx 1-Cre（KC）小鼠模型Agr 2诱导先于肿瘤前病变的形成，并且在工程化LSL-KrasG 12 D; Pdx 1-Cre; Agr 2 −/−小鼠中Agr 2缺失在很大程度上抑制了其发展。在体外，衣霉素诱导的内质网（ER）应激刺激了KRAS野生型正常胰腺细胞以及KRAS突变胰腺癌细胞中的AGR 2表达，并且对于ER稳态至关重要。未折叠的蛋白反应蛋白GRP 78、ATF 6和XBP 1 s在CP和PDAC瘤周组织中表达，但与AGR 2相反，它们的表达在TC和PanIN形成期间被关闭。实时PCR和ELISA分析表明，ER应激诱导胰腺正常细胞、癌细胞和星状细胞中的促炎表型。此外，AGR 2的表达可通过ER应激和促炎症在不同胰腺细胞类型之间的旁分泌转移来诱导。我们的研究结果表明，在ER应激和炎症前肿瘤胰腺中诱导的AGR 2是癌症祖细胞的潜在标志物，在PDAC启动中具有重要的功能作用。
The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-KrasG12D;Pdx1-Cre (KC) mouse model Agr2 induction preceded the formation of pre-neoplastic lesions and their development was largely inhibited by Agr2 deletion in engineered LSL-KrasG12D;Pdx1-Cre; Agr2−/− mice. In vitro, AGR2 expression was stimulated by tunicamycin-induced endoplasmic reticulum (ER) stress in both KRAS wild-type normal pancreas cells, as well as in KRAS mutated pancreatic cancer cells and was essential for ER homoeostasis. The unfolded protein response proteins GRP78, ATF6 and XBP1s were found expressed in CP and PDAC peritumoral tissues, but in contrast to AGR2, their expression was switched off during TC and PanIN formation. Real-time PCR and ELISA analyses showed that ER stress induced a pro-inflammatory phenotype in pancreatic normal, cancer and stellate cells. Moreover, AGR2 expression was inducible by paracrine transfer of ER stress and pro-inflammation between different pancreatic cell types. Our findings demonstrate that AGR2 induced in ER-stressed and inflammatory pre-neoplastic pancreas is a potential marker of cancer progenitor cells with an important functional role in PDAC initiation.