Zhao Weidong, Hisamuddin Irfan M, Nandan Mandayam O, Babbin Brian A, Lamb Neil E, Yang Vincent W
Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA.
Oncogene. 2004 Jan 15;23(2):395-402. doi: 10.1038/sj.onc.1207067.
Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that flank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in five of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5'-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21(WAF1/Cip1) promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.
Krüppel样因子4（KLF4或GKLF）是细胞周期的抑制剂。编码KLF4的基因定位于9号染色体q臂，先前研究表明其在结直肠癌（CRC）中存在等位基因缺失。在本研究中，我们发现30例CRC样本中KLF4 mRNA的平均水平是配对正常结肠组织的52%。同样，6种已建立的CRC细胞系中KLF4 mRNA和蛋白水平显著低于未转化的结肠上皮细胞系。使用位于KLF4基因座两侧的高度多态性DNA标记，我们在8例手术切除的CRC标本中的2例发现了杂合性缺失（LOH）的证据。此外，在6种CRC细胞系中的5种观察到LOH，另有1种细胞系在KLF4基因中表现为半合子缺失。我们还发现，在部分切除的CRC标本和细胞系中，KLF4的5'非翻译区发生了高甲基化。最后，在检测的3种CRC细胞系中的2种中，KLF4的开放阅读框包含几个点突变，导致激活p21（WAF1/Cip1）启动子的能力减弱。这些发现表明KLF4是CRC中一种潜在的肿瘤抑制基因。
