Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression
Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression
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DOI：
10.1158/0008-5472.can-04-3619
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Xie, KP
中科院分区：
文献类型：
--
作者：
Wei, DY;Gong, WD;Xie, KP
Kruppel-like factor 4 （KLF4）在肠、皮肤等上皮组织中高度表达。然而，KLF4在人胃癌发生发展中的作用尚不清楚。本研究表明，与正常胃粘膜相比，KLF4蛋白在原发肿瘤，特别是淋巴结转移中表达降低或缺失。此外，KLF4在原发肿瘤中的表达缺失与生存率低显著相关，在多变量分析中也是一个独立的预后指标。与此一致的是，大多数人胃癌细胞系在RNA和蛋白质水平上都表现出KLF4表达的缺失或显著降低。强制恢复KLF4表达在体外显著抑制细胞生长，在原位胃癌动物模型中显著减弱肿瘤生长和完全消除转移。机制研究表明，启动子超甲基化和半合子缺失导致KLF4表达下调，诱导凋亡导致KLF4具有抗肿瘤活性。总之，我们的数据提供了第一个临床和偶然的证据和潜在的机制，即YLF4表达的改变在胃癌的发生和进展中起关键作用。
Kruppel-like factor 4 (KLF4) is highly expressed in epithelial tissues such as the gut and skin. However, the role of KLF4 in human gastric cancer development and progression is unknown. Here we show that KLF4 protein expression was decreased or lost in primary tumors and, in particular, lymph node metastases when compared with that in normal gastric mucosa. Moreover, loss of KLF4 expression in the primary tumors was significantly associated with poor survival, and also an independent prognostic marker in a multivariate analysis. Consistently, most human gastric cancer cell lines exhibited loss of or a substantial decrease in KLF4 expression at both RNA and protein levels. Enforced restoration of KLF4 expression resulted in marked cell growth inhibition in vitro and significantly attenuated tumor growth and total abrogation of metastasis in an orthotopic animal model of gastric cancer. Mechanism studies indicated that promoter hyper-methylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4. Collectively, our data provide first clinical and casual evidence and potential mechanism that the alteration of YLF4 expression plays a critical role in gastric cancer development and progression.