SWI/SNF component ARID1A restrains pancreatic neoplasia formation.
SWI/SNF component ARID1A restrains pancreatic neoplasia formation.
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SWI/SNF成分ARID1A限制胰腺肿瘤形成。
DOI：
10.1136/gutjnl-2017-315490
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发表时间：
2019-07
期刊：
影响因子：
24.5
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Wang SC;Nassour I;Xiao S;Zhang S;Luo X;Lee J;Li L;Sun X;Nguyen LH;Chuang JC;Peng L;Daigle S;Shen J;Zhu H
ARID1A 在胰腺导管腺癌 (PDAC) 中常见突变，但 ARID1A 突变对胰腺的功能影响尚不清楚。了解驱动 PDAC 形成的分子机制可能会带来新的疗法。在小鼠中建立了同时条件性 Arid1a 缺失和 Kras 激活突变的模型。小干扰 RNA (siRNA) 和 CRISPR/Cas9 用于消除人胰腺导管上皮细胞中的 ARID1A。我们发现小鼠胰腺特异性 Arid1a 缺失足以诱发炎症、胰腺上皮内瘤变 (PanIN) 和粘液性囊肿。同时 Kras 激活加速了类似于导管内乳头状粘液性肿瘤的囊肿的发展。谱系特异性 Arid1a 缺失证实了区室特异性肿瘤抑制作用。导管特异性 Arid1a 缺失促进导管扩张，偶尔出现囊肿和 PDAC 形成。杂合腺泡特异性 Arid1a 缺失导致 PanIN 和 PDAC 形成加速，且生存率较差。 RNA-seq 显示 Arid1a 丢失诱导与 Myc 活性和蛋白质翻译相关的基因网络。人胰腺导管上皮细胞中的 ARID1A 敲低诱导 MYC 表达和蛋白质合成增加，而 MYC 敲低则消除了这一现象。针对 H3K27ac 的 ChIP-seq 证明激活的增强子/启动子有所增加。 Arid1a 以区室特异性方式抑制胰腺肿瘤形成。在导管细胞中，这一过程似乎与 MYC 促进的蛋白质合成有关。
ARID1A is commonly mutated in pancreatic ductal adenocarcinoma (PDAC), but the functional effects of ARID1A mutations in the pancreas are unclear. Understanding the molecular mechanisms that drive PDAC formation may lead to novel therapies. Concurrent conditional Arid1a deletion and Kras activation mutations were modelled in mice. Small-interfering RNA (siRNA) and CRISPR/Cas9 were used to abrogate ARID1A in human pancreatic ductal epithelial cells. We found that pancreas-specific Arid1a loss in mice was sufficient to induce inflammation, pancreatic intraepithelial neoplasia (PanIN) and mucinous cysts. Concurrent Kras activation accelerated the development of cysts that resembled intraductal papillary mucinous neoplasm. Lineage-specific Arid1a deletion confirmed compartment-specific tumour-suppressive effects. Duct-specific Arid1a loss promoted dilated ducts with occasional cyst and PDAC formation. Heterozygous acinar-specific Arid1a loss resulted in accelerated PanIN and PDAC formation with worse survival. RNA-seq showed that Arid1a loss induced gene networks associated with Myc activity and protein translation. ARID1A knockdown in human pancreatic ductal epithelial cells induced increased MYC expression and protein synthesis that was abrogated with MYC knockdown. ChIP-seq against H3K27ac demonstrated an increase in activated enhancers/promoters. Arid1a suppresses pancreatic neoplasia in a compartment-specific manner. In duct cells, this process appears to be associated with MYC-facilitated protein synthesis.
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哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
影响因子：
7.5
作者：
Agaimy, Abbas;Haller, Florian;Kloeppel, Guenter
通讯作者：
Kloeppel, Guenter
影响因子：
7.7
作者：
Harries, Lorna W.;Locke, Jonathan M.;Hattersley, Andrew T.
通讯作者：
Hattersley, Andrew T.
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE