The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis
The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis
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DOI：
10.1101/gad.204453.112
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发表时间：
2013-02-01
影响因子：
10.5
通讯作者：
Rustgi, Anil K.
中科院分区：
文献类型：
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作者：
Reichert, Maximilian;Takano, Shigetsugu;Rustgi, Anil K.
胰腺外分泌细胞的可塑性可以在发育、胰腺炎和随后的再生以及转化过程中观察到。例如，腺泡导管化生（ADM）发生在急性胰腺炎期间，可能被视为胰腺上皮内瘤变（PanIN）和胰腺导管腺癌（PDAC）发展的前奏。为了阐明与导管发育、ADM和正常细胞向PanIN病变进展重叠的调控过程，我们采用了一种系统的方法来鉴定Prrx 1配对同源结构域Prrx 1转录因子作为这些过程中高度调控的基因。Prrx 1注释Prrx 1creER（T2）-IRES-GFP小鼠中胰腺导管上皮细胞的亚群。此外，分选的Prrx 1（+）细胞在慢性胰腺炎期间具有自我更新和扩增的能力。Prrx 1a和Prrx 1b两种亚型分别调节胰腺癌细胞的迁移和侵袭。此外，Prrx 1b在循环胰腺细胞中富集（Pdx 1cre;LSL-Kras（G12 D/+）;p53（fl/+）; R26 YFP）。有趣的是，Prrx 1b亚型，这也是诱导ADM，结合Sox 9启动子和积极调节Sox 9的表达。这表明了一个新的分层方案，Prrx 1-Sox 9轴可能会影响腺泡导管化生和再生的出现。此外，我们的数据提供了一个可能的解释，为什么胰腺癌倾向于导管的命运。
Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creER(T2)-IRES-GFP mice. Furthermore, sorted Prrx1(+) cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-Kras(G12D/+);p53(fl/+);R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.