Kruppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis
Kruppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis
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DOI：
10.1053/j.gastro.2007.10.023
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发表时间：
2008-01-01
期刊：
影响因子：
29.4
通讯作者：
Yang, Vincent W.
中科院分区：
文献类型：
--
作者：
Nandan, Mandayam O.;Mcconnell, Beth B.;Yang, Vincent W.
背景与目的：Kruppel样因子5（KLF 5）是一种调节细胞增殖的锌指转录因子。致癌性KRAS突变通常在结直肠癌中发现。我们的目的是确定KLF 5是否在肠道肿瘤发生期间介导KRAS功能。研究方法：在用诱导型KRAS（V12 G）稳定转染的IEC-6肠上皮细胞中检测KLF 5对增殖和转化的影响。在来自表达KRAS（V12 G）der绒毛蛋白启动子的转基因小鼠的肠肿瘤和具有突变的KRAS的人结直肠癌中检查KLF 5表达。结果如下：在IEC-6细胞中诱导KRAS（V12 G）导致KLF 5表达增加，伴随着增殖和锚定非依赖性生长速率增加。通过丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK）抑制剂或KLF 5特异性小干扰RNA抑制KLF 5表达可降低增殖和锚定非依赖性生长，尽管KRAS（V12 G）诱导。具有突变KRAS的人结直肠癌细胞系含有高水平的KLF 5，并且通过MEK抑制剂或KL 175小干扰RNA减少KLF 5也导致增殖和转化减少。在体内，来自villin-KRAS转基因小鼠（V12 G）的肠道肿瘤和具有突变KRAS的人原发性结直肠癌均含有高水平的KLF 5和增殖标记物Ki 67的染色增加。结论：在体外和体内肠道肿瘤中，KLF 5蛋白水平升高与激活KRAS突变密切相关。抑制肿瘤细胞中的KLF 5表达导致增殖和转化活性的速率显著降低。我们的结论是，KLF 5是一个重要的介导的致癌KRAS转化功能在肠道肿瘤的发生。
Background & Aims: Kruppel-like factor 5 (KLF5) is a zinc finger-transcription factor that regulates cell proliferation. Oncogenic KRAS mutations are commonly found in colorectal cancers. We aimed to determine whether KLF5 mediates KRAS functions during intestinal tumorigenesis. Methods: The effects of KLF5 on proliferation and transformation were examined in IEC-6 intestinal epithelial cells stably transfected with inducible KRAS(V12G). KLF5 expression was examined in intestinal tumors derived from transgenic mice expressing KRAS(V12G) der villin promoter and in human colorectal cancers with mutated KRAS. Results: Induction of KRAS (V12G) in IEC-6 cells resulted in increased expression of KLF5, accompanied by increased rates of proliferation and anchorage-independent growth. Inhibition of KLF5 expression by mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors or KLF5-specific small interfering RNA reduced proliferation and anchorage-independent growth despite KRAS(V12G) induction. Human colorectal cancer cell lines with mutated KRAS contained high levels of KLF5 and reduction of KLF5 by MEK inhibitors or KL175 small interfering RNA also led to reduced proliferation and transformation. In vivo, both intestinal tumors derived from mice transgenic for villin-KRAS(V12G) and human primary colorectal cancers with mutated KRAS contained high levels of KLF5 and increased staining of the proliferative marker Ki67. Conclusions: Elevated levels of KLF5 protein are strongly correlated with activating KRAS mutations in intestinal tumors in vitro and in vivo. Inhibition of KLF5 expression in tumor cells resulted in significantly reduced rates of proliferation and transforming activities. We conclude that KLF5 is an important mediator of oncogenic KRAS transforming functions during intestinal tumorigenesis.