Shi Guanglu, Zhu Liqin, Sun Yan, Bettencourt Ryan, Damsz Barbara, Hruban Ralph H, Konieczny Stephen F
Department of Biological Sciences and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-2064, USA.
Gastroenterology. 2009 Apr;136(4):1368-78. doi: 10.1053/j.gastro.2008.12.066. Epub 2009 Jan 9.
BACKGROUND & AIMS: Invasive pancreatic ductal adenocarcinoma is thought to originate from duct-like lesions called pancreatic intraepithelial neoplasia (PanIN). PanINs progress from low grade (PanIN-1) to high grade (PanIN-3) as the cells attain molecular alterations to key regulatory genes, including activating mutations in the KRAS protooncogene. Despite a well-documented progression model, our knowledge of the initiator cells of PanINs and the transcriptional networks and signaling pathways that impact PanIN formation remains incomplete.
In this study, we examined the importance of the acinar-restricted transcription factor Mist1 to KrasG12D-induced mouse PanIN (mPanIN) formation in 3 different mouse models of pancreatic cancer.
In the absence of Mist1 (Mist1KO), KrasG12D-expressing mice exhibited severe exocrine pancreatic defects that were rescued by ectopic expression of Mist1 in acinar cells. mPanIN development was greatly accelerated in Mist1KO/KrasG12D/+ pancreata, and in vitro assays revealed that Mist1KO acinar cells were predisposed to convert to a ductal phenotype and activate epidermal growth factor receptor (EGFR) and Notch-signaling pathways.
We propose that convergence of EGFR, Notch, and Kras pathways in acinar cells lacking Mist1 leads to enhanced mPanIN formation.
侵袭性胰腺导管腺癌被认为起源于称为胰腺上皮内瘤变（PanIN）的导管样病变。随着细胞获得关键调控基因的分子改变，包括KRAS原癌基因的激活突变，PanIN从低级别（PanIN-1）进展到高级别（PanIN-3）。尽管有一个记录完善的进展模型，但我们对PanIN起始细胞以及影响PanIN形成的转录网络和信号通路的了解仍不完整。
在本研究中，我们在3种不同的胰腺癌小鼠模型中研究了腺泡特异性转录因子Mist1对KrasG12D诱导的小鼠PanIN（mPanIN）形成的重要性。
在缺乏Mist1（Mist1KO）的情况下，表达KrasG12D的小鼠表现出严重的胰腺外分泌缺陷，腺泡细胞中Mist1的异位表达可挽救这些缺陷。在Mist1KO/KrasG12D/+胰腺中，mPanIN的发展大大加速，体外试验表明，Mist1KO腺泡细胞易于转变为导管表型并激活表皮生长因子受体（EGFR）和Notch信号通路。
我们提出，在缺乏Mist1的腺泡细胞中，EGFR、Notch和Kras信号通路的汇聚导致mPanIN形成增强。
