Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.
Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.
复制标题
DOI：
10.1096/fj.201801176r
复制
发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Oshima M
中科院分区：
文献类型：
--
作者：
Oshima H;Kok SY;Nakayama M;Murakami K;Voon DC;Kimura T;Oshima M
信号转导和转录激活因子3 （Stat3）已被证明在肠再生和结肠炎相关结肠癌发生中发挥作用。然而，Stat3在wnt驱动的散发性肠道肿瘤发生中的作用仍然知之甚少。我们利用Stat3∆IEC小鼠肠上皮细胞进行类器官培养实验，研究Stat3在肠再生和肿瘤发生中的作用。Stat3的破坏显著抑制了肠黏膜的再生和类器官的形成，而Wnt的激活弥补了这一抑制作用。此外，一旦类器官被恢复，类器官的生长就不再需要Stat3。这些结果表明，Stat3和Wnt信号在肠再生的早期阶段协同保护上皮细胞。相比之下，在大肠腺瘤性息肉病（Apc）Δ716和Apc∆716 Tgfbr2∆IEC小鼠中，Stat3的破坏并未抑制肠道肿瘤的发生，这表明Wnt激活驱动的肠道肿瘤发生不需要Stat3。机制上，Itga5和Itga6因Stat3的破坏而下调，局灶黏附激酶（FAK）的激活也受到抑制。值得注意的是，FAK抑制剂抑制野生型上皮细胞的类器官形成。这些结果表明Stat3通过激活整合素信号和下游FAK通路对上皮细胞的存活是必不可少的；然而，Wnt信号激活的正常或肿瘤上皮细胞不需要。-大岛，H.；角，s .；Nakayama， M.，村上，K., Voon, d.c.c。Stat3对于损伤诱导的隐窝再生是必不可少的，但对于wnt驱动的肠道肿瘤发生却不是。
Signal transducer and activator of transcription 3 (Stat3) has been shown to play a role in intestinal regeneration and colitis-associated colon carcinogenesis. However, the role of Stat3 in the Wnt-driven sporadic intestinal tumorigenesis remains poorly understood. We examined the roles of Stat3 in intestinal regeneration and tumorigenesis by organoid culture experiments using Stat3∆IEC mouse–derived intestinal epithelial cells in which Stat3 was disrupted. The regeneration of intestinal mucosa and organoid formation were significantly suppressed by Stat3 disruption, which was compensated by Wnt activation. Furthermore, once organoids were recovered, Stat3 was no longer required for organoid growth. These results indicate that Stat3 and Wnt signaling cooperatively protect epithelial cells at the early phase of intestinal regeneration. In contrast, intestinal tumorigenesis was not suppressed by Stat3 disruption in adenomatous polyposis coli (Apc)Δ716 and Apc∆716 Tgfbr2∆IEC mice, thus indicating that Stat3 is not required for Wnt activation–driven intestinal tumorigenesis. Mechanistically, Itga5 and Itga6 were down-regulated by Stat3 disruption, and focal adhesion kinase (FAK) activation was also suppressed. Notably, FAK inhibitor suppressed the organoid formation of wild-type epithelial cells. These results indicate that Stat3 is indispensable for the survival of epithelial cells through the activation of integrin signaling and the downstream FAK pathway; however, it is not required for the Wnt signaling-activated normal or tumor epithelial cells.—Oshima, H., Kok, S.-Y., Nakayama, M., Murakami, K., Voon, D. C.-C., Kimura, T., Oshima, M. Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.