KLF5 Regulates the Integrity and Oncogenicity of Intestinal Stem Cells
KLF5 Regulates the Integrity and Oncogenicity of Intestinal Stem Cells
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DOI：
10.1158/0008-5472.can-13-2574
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发表时间：
2014-05-15
期刊：
影响因子：
11.2
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Nakaya, Takeo;Ogawa, Seishi;Nagai, Ryozo
肠上皮通过涉及常驻干细胞（包括Lgr 5（+）隐窝基底柱状细胞）的自我更新过程来维持体内平衡，但核心机制及其对肠癌的贡献尚未完全确定。在这项研究中，我们研究了KLF 5的假设作用，KLF 5是一种锌指转录因子，对维持胚胎和诱导多能干细胞的完整性至关重要，在小鼠肠道干细胞完整性和癌症中。Klf 5对肠干细胞的完整性和致癌性转化是不可或缺的。在小鼠中，Lgr 5（+）干细胞中Klf 5的可诱导缺失以与β-连环蛋白（Catnb）的核定位相关的方式抑制其增殖和存活，从而在肠隐窝中产生异常凋亡细胞。此外，在Lgr 5（+）干细胞中，β-连环蛋白致癌突变体的特异性表达导致的致死性腺瘤和癌的产生，在相同细胞中被Klf 5缺失完全抑制。鉴于Wnt/β-catenin通路的激活是人类结直肠癌中最常改变的通路，我们的研究结果表明KLF 5在干细胞水平上作为肠道肿瘤发生的基本核心调节因子，并且他们建议KLF 5靶向作为根除结直肠癌中干细胞样细胞的合理策略。(C)2014年AACR。
The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of beta-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of beta-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/beta-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer. (C) 2014 AACR.