EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis.
EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis.
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DOI：
10.18632/oncotarget.20601
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Fukayama M
中科院分区：
文献类型：
--
作者：
Tanaka M;Ishikawa S;Ushiku T;Morikawa T;Isagawa T;Yamagishi M;Yamamoto H;Katoh H;Takeshita K;Arita J;Sakamoto Y;Hasegawa K;Kokudo N;Fukayama M
外泌体中的Glypican-1 （GPC1）蛋白最近被确定为早期检测胰腺导管腺癌（PDAC）的生物标志物。通过免疫组化分析和体外实验评估GPC1作为PDAC生物标志物的有效性，揭示GPC1在胰腺癌发生中的生物学作用，明确GPC1的调控机制。正常胰管中通常不存在异常过表达的GPC1蛋白，是人类PDAC前体、PDAC和胰腺癌间质中广泛存在的标志物。在导管内乳头状粘液瘤（IPMN）中，GPC1倾向于胃型IPMN阳性。在所有gpc1阳性IPMN病例和三分之一gpc1阴性IPMN病例中均发现KRAS突变。在胰腺细胞系中，GPC1缺失引起细胞生长和迁移的显著抑制，提示其致癌作用。在胰腺细胞系中，GPC1缺失上调了与细胞周期阻滞相关的分子。此外，KRAS和ecotropic viral integration site 1 （EVI1）癌蛋白上调了GPC1的表达。在一项临床队列研究中，GPC1过表达与胰腺癌预后无关。综上所述，这些发现表明建立GPC1阈值检测胰腺恶性肿瘤的必要性，因为GPC1在低级别PDAC前体中也过表达，而这些PDAC前体并不总是恶性的。我们的研究还揭示了胰腺癌发生的一个新方面：KRAS和EVI1这两个胰腺癌早期发生的重要分子正调控GPC1的表达，并可能促进胰腺癌的发生。
Glypican-1 (GPC1) protein in exosomes was recently identified as a biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analyses and in vitro assays were conducted to assess the usefulness of GPC1 as a PDAC biomarker, to reveal the biological role of GPC1 in pancreatic carcinogenesis, and to ascertain the regulation mechanism of GPC1. An aberrant overexpression of GPC1 protein which is usually absent in normal pancreatic duct, was a widespread marker across the full spectrum of human PDAC precursors, PDAC, and pancreatic cancerous stroma. In intraductal papillary-mucinous neoplasms (IPMNs), GPC1 tended to be positive in gastric-type IPMN. KRAS mutations were found in all GPC1-positive IPMN cases and in one-third of GPC1-negative IPMN cases. In pancreatic cell lines, GPC1 depletion caused remarkable inhibition of cell growth and migration, suggesting its oncogenic roles. GPC1 depletion upregulated the molecules associated with cell cycle arrest in pancreatic cell lines. Furthermore, KRAS and ecotropic viral integration site 1 (EVI1) oncoprotein upregulated GPC1 expression. In a clinical cohort, GPC1 overexpression was not correlated with pancreatic cancer prognosis. Taken together, these findings suggest the necessity of establishing a threshold of GPC1 value for detecting pancreatic malignancy because GPC1 is overexpressed even in low-grade PDAC precursors which do not always become malignant. Our study also reveals a new aspect of pancreatic carcinogenesis: KRAS and EVI1, two important molecules in early phases of pancreatic carcinogenesis, positively regulate GPC1 expression and likely promote pancreatic carcinogenesis.
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DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
影响因子：
64.8
作者：
Thayer, SP;di Magliano, MP;Hebrok, M
通讯作者：
Hebrok, M
影响因子：
29.4
作者：
Murphy SJ;Hart SN;Lima JF;Kipp BR;Klebig M;Winters JL;Szabo C;Zhang L;Eckloff BW;Petersen GM;Scherer SE;Gibbs RA;McWilliams RR;Vasmatzis G;Couch FJ
通讯作者：
Couch FJ
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
5.3
作者：
Qiao, Dianhua;Meyer, Kristy;Friedl, Andreas
通讯作者：
Friedl, Andreas