Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
EMBO J. 2019 Jul 1;38(13):e101067. doi: 10.15252/embj.2018101067. Epub 2019 May 31.
A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-β) 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 , culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-β 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 /MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in Kras ;Tgif1 mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains Kras -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-β signaling might act to accelerate PDAC progression rather than to suppress its initiation.
TGIF1 的一个主要功能是抑制转化生长因子β（TGF-β）信号，其失活被认为对胰腺导管腺癌（PDAC）的进展至关重要，例如这种恶性肿瘤中频繁缺失肿瘤抑制基因 SMAD4。令人惊讶的是，我们发现，尽管 TGF-β信号被解除抑制，但在致癌性 Kras 背景下遗传失活 Tgif1 最终导致高度侵袭性和转移性 PDAC 的发展。机制实验表明，TGIF1 与 Twist1 结合并抑制 Twist1 的表达和活性，而这种功能在绝大多数人类 PDAC 中被 Kras/MAPK 介导的 TGIF1 磷酸化所抑制。在 Kras;Tgif1 小鼠中消除 Twist1 完全阻止了 PDAC 的形成，提供了 TGIF1 通过拮抗 Twist1 来抑制 Kras 驱动的 PDAC 的原理证明。总的来说，这些发现指出 TGIF1 是 PDAC 中的一个潜在肿瘤抑制因子，并进一步表明 TGF-β 信号的持续激活可能加速 PDAC 的进展，而不是抑制其起始。
