ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.
ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.
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DOI：
10.1016/j.stem.2013.04.006
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发表时间：
2013-06-06
期刊：
影响因子：
23.9
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
--
作者：
Myant, Kevin B.;Cammareri, Patrizia;McGhee, Ewan J.;Ridgway, Rachel A.;Huels, David J.;Cordero, Julia B.;Schwitalla, Sarah;Kalna, Gabriela;Ogg, Erinn-Lee;Athineos, Dimitris;Timpson, Paul;Vidal, Marcos;Murray, Graeme I.;Greten, Florian R.;Anderson, Kurt I.;Sansom, Owen J.
大肠腺瘤性息肉病（APC）基因在大多数结直肠癌（CRC）中发生突变。APC的丧失导致组成性活性WNT信号传导、过度增殖和肿瘤发生。鉴定APC丢失后促进肿瘤发生的途径对于治疗开发是重要的。在这里，我们表明，RAC 1是APC损失后的肿瘤发生的关键介质。我们发现RAC 1是LGR 5肠干细胞（ISC）签名扩增、祖细胞过度增殖和转化所必需的。从机制上讲，RAC 1驱动的ROS和NF-κB信号转导介导了这些过程。总之，这些数据强调了RAC 1触发的ROS产生和NF-κB活化是CRC起始的关键事件。RAC 1是APC缺失后肿瘤发生所必需的LGR 5 ISC转化需要RAC 1 RAC 1驱动的ROS产生和NF-κB活化是CRC起始所必需的。该研究表明，RAC 1介导的ROS产生和NF-κ B活化是APC基因缺失后LGR 5干细胞扩增和结直肠癌起始所必需的。
The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-κB signaling mediate these processes. Together, these data highlight that ROS production and NF-κB activation triggered by RAC1 are critical events in CRC initiation. RAC1 is required for tumorigenesis after APC loss LGR5 ISC transformation requires RAC1 RAC1-driven ROS production and NF-κB activation are required for CRC initiation This study demonstrates that RAC1-mediated ROS production and NF-KB activation is required for LGR5 stem cell expansion and colorectal cancer initiation after loss of the APC gene.
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