The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis
The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis
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DOI：
10.1172/jci94287
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发表时间：
2018-08-01
影响因子：
15.9
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
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作者：
Tsuda, Motoyuki;Fukuda, Akihisa;Seno, Hiroshi
染色质重塑者Brahma相关基因1 （BRG1）在大约10%的人胰腺导管腺癌（pda）中沉默。我们之前的研究表明，BRG1抑制导管内胰腺粘液瘤（IPMN）的形成，IPMN衍生的PDA起源于导管细胞。然而，BRG1在起源于腺泡细胞的胰腺上皮内瘤变衍生（panin衍生）PDA中的作用仍然难以捉摸。在这里，我们发现Ptf1a-Cre（ER）的腺泡细胞中Brg1的排他消除；喀斯特(G12D);Brg1（fl/fl）小鼠在p53突变不存在的情况下，能抑制腺泡到导管化生（ADM）和PanIN的形成，而p53突变存在时，能抑制PDA的形成。BRG1结合到Sox9启动子的区域来调节其表达，并且对于在腺泡细胞中募集上游调节因子（包括PDX1）到Sox9启动子和增强子至关重要。在brg1缺失的adm /PanINs中，SOX9表达下调。值得注意的是，在KBC小鼠中，Sox9的过表达消除了这种panin减弱的表型。此外，使用双重组酶系统对建立的PanIN进行Brg1缺失，导致小鼠病变消退。最后，在人pda中，BRG1表达与SOX9表达相关。综上所述，BRG1通过SOX9的正调控对PanIN的启动和进展至关重要。因此，BRG1/SOX9轴是panin衍生PDA的潜在靶点。
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-Cre(ER); Kras(G12D); Brg1(fl/fl) mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.