The biological features of PanIN initiated from oncogenic Kras mutation in genetically engineered mouse models
The biological features of PanIN initiated from oncogenic Kras mutation in genetically engineered mouse models
复制标题
基因工程小鼠模型中由致癌 Kras 突变引发的 PanIN 的生物学特征
DOI：
10.1016/j.canlet.2013.07.010
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发表时间：
2013-10-01
期刊：
影响因子：
9.7
通讯作者：
Wang, Lifu
中科院分区：
文献类型：
--
作者：
Shen, Ruizhe;Wang, Qi;Wang, Lifu
胰腺上皮内瘤变（PanIN）是胰腺最常见的癌前病变。进一步了解PanIN逐步进展中的生物学行为和分子遗传学改变对于胰腺导管腺癌（PDAC）干预措施的发展是必要的。在这项研究中，我们分析了胰腺野生型和肿瘤组织的形态学特征、分子改变和生物学行为，包括PanIN细胞系SH-PAN（分离自Pdx-1-Cre; LSL-Kras（G12 D/+）小鼠）和PDAC细胞系DT-PCa（分离自Pdx-1-Cre; LSL-Kras（G12 D/+）; LSL-Tp 53（R172 H/+）小鼠）的分析。结果显示Kras（G12 D）诱导导管病变PanINs。在低级别PanIN中观察到埃格、Her-2/Neu、p-MAPK和β-Catenin的表达增加。TP 53在野生型和低级别PanIN中不表达，然而，在高级别PanIN中观察到表达增加。此外，SH-PAN细胞没有表现出任何集落形成，并显示出显着较低的迁移和侵袭能力与DT-PCa细胞相比。值得注意的是，我们首先发现PPP 2 R2 A（蛋白磷酸酶2，调节亚基B，α）的表达在SH-PAN细胞中显著高于DT-PCa细胞，并且在172个瘤周正常人胰腺组织中的96个和36个人低或中等级别PanIN组织中的20个中高，然而，术后20例人类高级别PanIN组织中的12例和172例人类PDAC组织中的124例中的表达较弱或可忽略不计。PPP 2 R2 A的表达似乎与临床生存相关。Kras（G12 D）驱动的PanIN具有致瘤性，但不会发生恶性转化，PPP 2 R2 A在PDAC中的表达降低可能为胰腺癌的干预提供新的靶点。(C)2013作者由爱思唯尔有限公司出版。保留所有权利。
Pancreatic intraepithelial neoplasia (PanIN) is the most common premalignant lesion of the pancreas. Further understanding of the biological behavior and molecular genetic alterations in the stepwise progression of PanINs is necessary toward the development of pancreatic ductal adenocarcinoma (PDAC) interventions. In this study, we analyzed the morphological characteristics, molecular alterations, and biological behavior of pancreatic wild-type and neoplasia tissues, including analysis of PanIN cell line SH-PAN (isolated from Pdx-1-Cre; LSL-Kras(G12D/+) mouse) and PDAC cell line DT-PCa (isolated from Pdx1-Cre; LSL-Kras(G12D/+); LSL-Tp53(R172H/+) mouse). Results show that Kras(G12D) induces ductal lesion PanINs. Increased expression of EGER, Her-2/Neu, p-MAPK and beta-Catenin was observed in low-grade PanINs. Tp53 was not expressed in wild-type and low-grade PanINs, however, increased expression was observed in high-grade PanINs. Furthermore, SH-PAN cells did not exhibit any colony formation and showed significantly lower migration and invasion ability compared with DT-PCa cells. Notably, we first found PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha) expression was significantly higher in SH-PAN cells than DT-PCa cells, and was high in 96 of 172 peritumoral normal human pancreatic tissues and 20 of 36 human low- or middle-grade PanIN tissues, whereas, was weak or negligible in 12 of 20 human high-grade PanIN tissues and 124 of 172 human PDAC tissues post-operation. The expression of PPP2R2A appears to be correlated with clinical survival. Taken together, Kras(G12D) - driven PanIN showed the tumorigenic ability, however, did not undergo a malignant transformation, and decreased expression of PPP2R2A in PDACs may provided a new target for pancreatic carcinoma intervention. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.