Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma.
Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma.
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DOI：
10.1371/journal.pone.0052133
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kissil JL
中科院分区：
文献类型：
--
作者：
Avila JL;Troutman S;Durham A;Kissil JL
胰腺导管腺癌被认为是由称为胰腺上皮内瘤变（PanIN）的前驱病变引起的。小鼠模型已经证明，激活的K-ras靶向表达到胰腺中的成熟腺泡细胞诱导PanIN病变的自发发展;这意味着腺泡到导管化生（ADM）是该过程中的关键事件。最近的研究表明Notch信号是ADM的关键调节因子。为了评估Notch 1是否是K-ras驱动ADM所必需的，我们采用了体内小鼠模型和体外外植体培养系统，其中K-ras的致癌等位基因被激活，同时Notch 1在腺泡细胞中被删除。我们的研究结果表明，致癌K-ras是足以驱动ADM在体外和体内，但Notch 1的损失有一个最小的影响，在这个过程中。有趣的是，虽然Notch 1在体内的丢失不影响观察到的PanIN病变的严重程度，但Notch 1缺失的小鼠中病变的总数更大。这表明Notch 1缺失使腺泡细胞更容易形成K-ras诱导的PanIN。
Pancreatic ductal adenocarcinoma is believed to arise from precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). Mouse models have demonstrated that targeted expression of activated K-ras to mature acinar cells in the pancreas induces the spontaneous development of PanIN lesions; implying acinar-to-ductal metaplasia (ADM) is a key event in this process. Recent studies suggest Notch signaling is a key regulator of ADM. To assess if Notch1 is required for K-ras driven ADM we employed both an in vivo mouse model and in vitro explant culture system, in which an oncogenic allele of K-ras is activated and Notch1 is deleted simultaneously in acinar cells. Our results demonstrate that oncogenic K-ras is sufficient to drive ADM both in vitro and in vivo but that loss of Notch1 has a minimal effect on this process. Interestingly, while loss of Notch1 in vivo does not affect the severity of PanIN lesions observed, the overall numbers of lesions were greater in mice with deleted Notch1. This suggests Notch1 deletion renders acinar cells more susceptible to formation of K-ras-induced PanINs.
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