Krüppel-Like Factor 5 Promotes Epithelial Proliferation and DNA Damage Repair in the Intestine of Irradiated Mice.
Krüppel-Like Factor 5 Promotes Epithelial Proliferation and DNA Damage Repair in the Intestine of Irradiated Mice.
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Krüppel 样因子 5 促进受辐射小鼠肠道上皮细胞增殖和 DNA 损伤修复
DOI：
10.7150/ijbs.13444
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发表时间：
2015
影响因子：
9.2
通讯作者：
Zhang XG
中科院分区：
文献类型：
--
作者：
Li M;Gu Y;Ma YC;Shang ZF;Wang C;Liu FJ;Cao JP;Wan HJ;Zhang XG
背景与目的：高剂量辐射可引起肠上皮细胞尤其是隐窝细胞DNA严重损伤，导致肠道损伤，但其分子机制尚不清楚。Krüppel样因子5（KLF 5）是一种含锌指的转录因子，可被各种应激刺激诱导，并参与细胞增殖和存活。本研究旨在探讨KLF 5在放射性肠损伤中的作用。方法：采用8或15戈伊全身照射（TBI）的野生型小鼠。采用免疫印迹法和免疫组化法检测受照小鼠小肠组织中KLF 5的含量和细胞定位。产生了KLF 5的卵巢特异性敲低的小鼠（Vil-Cre; Klf 5 fl/+小鼠），并将其对辐射的反应与对照进行比较。苏木精-伊红染色观察形态学变化。Ki 67免疫组化染色检测细胞增殖情况。使用微阵列研究KLF 5敲低后小肠的分子反应。结果：KLF 5表达与肠损伤的进展相关。肠道中KLF 5水平的降低与TBI后肠粘膜损伤增加和上皮细胞增殖减少有关。我们的芯片数据显示，KLF 5敲低下调基因的DNA损伤修复途径，如核苷酸切除修复，错配修复，非同源末端连接和范可尼贫血途径，这可能表明一个新的功能KLF 5。结论：我们的研究表明，KLF 5可能通过调节DNA修复途径来预防TBI所致的肠道损伤。KLF 5信号通路为放射性肠损伤的治疗提供了一个新的靶点。
BACKGROUND & AIMS: High doses of radiation induce severe DNA damage in intestinal epithelial cells, especially crypt cells, and cause intestinal injury, but the underlying molecular mechanisms remain unclear. Krüppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is induced by various stress stimuli and is involved in cell proliferation and survival. The role of KLF5 in radiation-induced intestinal injury was investigated here. METHODS: Wild type mice were treated with 8 or 15 Gy total body irradiation (TBI). KLF5 content and cellular localization in the small intestines of irradiated mice were detected by Western blot and immunohistochemical analysis. Mice with intestinal-specific knockdown of KLF5 (Vil-Cre; Klf5fl/+ mice) were generated and their response to radiation was compared with controls. Morphological changes were determined by hematoxylin and eosin staining. Proliferation was examined by Ki67 immunostaining. The molecular response of the small intestine after KLF5 knockdown was investigated using microarrays. RESULTS: KLF5 expression correlated with the progression of intestinal damage. Decreased levels of KLF5 in the gut were associated with increased damage to the intestinal mucosa and reduced epithelial proliferation after TBI. Our microarray data disclosed that KLF5 knockdown down-regulated genes related to DNA damage repair pathways such as nucleotide excision repair, mismatch repair, non-homologous end joining and the Fanconi anemia pathway, which may suggest a novel function of KLF5. CONCLUSIONS: Our study illustrates that KLF5 may modulate DNA repair pathways to prevent intestinal injury induced by TBI. KLF5 signaling provides a novel field for identification of potential therapeutic targets for the treatment of radiation-induced intestinal damage.