TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma
TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma
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DOI：
10.15252/embj.2018101067
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发表时间：
2019-07-01
期刊：
影响因子：
11.4
通讯作者：
Atfi, Azeddine
中科院分区：
文献类型：
--
作者：
Parajuli, Parash;Singh, Purba;Atfi, Azeddine
TGIF1的一个突出功能是抑制转化生长因子β (tgf - β)信号，其失活被认为有助于胰腺导管腺癌（PDAC）的进展，如肿瘤抑制基因SMAD4在这种恶性肿瘤中的频繁丢失。令人惊讶的是，我们发现在致癌Kras（Kras(G12D)）的背景下，Tgif1的遗传失活最终导致高度侵袭性和转移性PDAC的发展，尽管去抑制tgf - β信号。机制实验表明，TGIF1与Twist1结合并抑制Twist1的表达和活性，而Kras(G12D)/ mapk介导的TGIF1磷酸化在绝大多数人类pdac中被抑制。Kras（G12D）中的烧蚀扭转1；Tgif1（KO）小鼠完全钝化了PDAC的形成，提供了Tgif1通过拮抗Twist1的能力抑制Kras（G12D）驱动的PDAC的原理证明。总的来说，这些发现指出TGIF1在PDAC中是一个潜在的肿瘤抑制因子，并进一步表明tgf - β信号的持续激活可能加速PDAC的进展，而不是抑制其启动。
A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-beta) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, Kras(G12D), culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-beta signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by Kras(G12D)/MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in Kras(G12D);Tgif1(KO) mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains Kras(G12D)-driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF-beta signaling might act to accelerate PDAC progression rather than to suppress its initiation.