YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.
YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.
复制标题
DOI：
10.1038/s41419-017-0244-8
复制
发表时间：
2018-02-02
影响因子：
9
通讯作者：
Zhi F
中科院分区：
文献类型：
--
作者：
Deng F;Peng L;Li Z;Tan G;Liang E;Chen S;Zhao X;Zhi F
上皮再生受损是溃疡性结肠炎（UC）的一个重要病理生理特征。是相关蛋白（YAP 1）似乎控制细胞增殖和分化。在本研究中，我们试图确定雅普在肠上皮细胞（IEC）自我更新，再生和肿瘤发生中的作用。我们首先观察到雅普在62.5%（45/72）的人UC组织中显著降低，并且在鼠结肠炎模型中在上皮再生期间显著增强。使用慢病毒感染，我们建立了YAP过表达（YAPWT）小鼠模型。然后，我们发现，在组织损伤后，YAPWT小鼠的上皮细胞自我更新能力增加，并大大恢复了肠隐窝结构。引人注目的是，这些小鼠在化学诱导的癌症中更容易患结肠炎相关癌症（CAC）。从机制上讲，雅普和β-连环蛋白在炎症后再生过程中显示出增加的核共定位。过表达雅普显著提高IEC的“伤口愈合”能力，并增加β-catenin和Wnt信号转导Lgr 5和细胞周期蛋白D1的转录靶点的表达，而在YAPWT细胞中沉默β-catenin减弱了这种作用。值得注意的是，我们观察到雅普可以直接与细胞核内的β-catenin相互作用，形成转录型雅普/β-catenin/TCF 4复合物，Lgr 5和cyclin D1被证实是该复合物的靶基因。与此相反，癌细胞增殖和肿瘤的发展受到磷酸模拟雅普突变体的抑制。总之，核YAP驱动的IEC增殖可以控制炎症后的上皮再生，并可能作为UC的潜在治疗靶点。然而，过度的雅普激活促进CAC的发展。
Impaired epithelial regeneration is a crucial pathophysiological feature of ulcerative colitis (UC). Yes-associated protein (YAP1) appears to control cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in intestinal epithelial cell (IEC) self-renewal, regeneration and tumorigenesis. We first observed that YAP was significantly reduced in 62.5% (45/72) of human UC tissues and it was dramatically enhanced during epithelial regeneration in a murine colitis model. Using lentiviral infection, we established a YAP-overexpression (YAPWT) mouse model. We then found that after tissue injury, YAPWT mice had increased epithelial cell self-renewal capacity and drastically restored intestinal crypt structure. Strikingly, these mice were more susceptible to colitis-associated cancer (CAC) in chemically induced carcinoma. Mechanistically, YAP and β-catenin showed increased nuclear co-localization during regeneration after inflammation. Overexpressing YAP significantly improved IEC ‘wound-healing’ ability and increased the expression of both β-catenin and the transcriptional targets of Wnt signalling Lgr5 and cyclin D1, whereas silencing β-catenin in YAPWT cells attenuated this effect. Remarkably, we observed that YAP could directly interact with β-catenin in the nucleus and formed a transcriptional YAP/β-catenin/TCF4 complex; Lgr5 and cyclin D1 were confirmed to be the target genes of this complex. In contrast, cancer cell proliferation and tumour development were suppressed by the phospho-mimetic YAP mutant. In summary, nuclear YAP-driven IEC proliferation could control epithelial regeneration after inflammation and may serve as a potential therapeutic target in UC. However, excessive YAP activation promoted CAC development.
登录
查看更多内容
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
23.9
作者：
Metcalfe, Ciara;Kljavin, Noelyn M.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
64.8
作者：
Gregorieff, Alex;Liu, Yu;Wrana, Jeffrey L.
通讯作者：
Wrana, Jeffrey L.
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
小鼠 CAC 模型中从结肠炎到 CRC 的基因表达变化的鉴定
影响因子：
3.7
作者：
Li X;Gao Y;Yang M;Zhao Q;Wang G;Yang YM;Yang Y;Liu H;Zhang Y
通讯作者：
Zhang Y