KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.
KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.
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DOI：
10.1158/0008-5472.can-15-1691
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发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Yan Y;Li Z;Kong X;Jia Z;Zuo X;Gagea M;Huang S;Wei D;Xie K
KLF 4和CD 44调节癌细胞的干细胞性，但它们在转移进展中的确切功能和作用尚不清楚。在这项研究中，我们使用诱导和基因工程的方法来评估这两个因素的活动是否在胰腺导管腺癌（PDA）相交。我们发现，从Klf 4flox/flox小鼠分离的PDA细胞中Klf 4的基因消融显著增加了CD 44的表达，并促进了干细胞样特性的获得，而四环素诱导的KLF 4表达在体外和体内抑制了这些特性。进一步的机制研究表明，KLF 4结合到CD 44启动子，负调控转录和CD 44变体（CD 44 v）的表达。此外，在人PDA组织中，KLF 4和CD 44的表达模式是相互排斥的，并且这种反向关系在人转移性胰腺肿瘤和PDA的原位小鼠模型中特别显著。综上所述，我们的研究结果表明，KLF 4在PDA细胞中作为肿瘤抑制因子，通过直接负调节CD 44来限制转移行为，为关注晚期肿瘤中靶向KLF 4激活的治疗方法的临床研究提供支持。
KLF4 and CD44 regulate cancer cell stemness, but their precise functions and roles in metastatic progression are not well understood. In this study, we used both inducible and genetic engineering approaches to assess whether the activities of these two factors intersect in pancreatic ductal adenocarcinoma (PDA). We found that genetic ablation of Klf4 in PDA cells isolated from Klf4flox/flox mice drastically increased CD44 expression and promoted the acquisition of stem-like properties, whereas tetracycline-inducible expression of KLF4 suppressed these properties in vitro and in vivo. Further mechanistic investigation revealed that KLF4 bound to the CD44 promoter to negatively regulate transcription and also the expression of the CD44 variant (CD44v). Moreover, in human PDA tissues, the expression patterns of KLF4 and CD44 were mutually exclusive, and this inverse relationship was particularly striking in human metastatic pancreatic tumors and in autochthonous mouse models of PDA. Taken together, our findings demonstrate that KLF4 acts as a tumor suppressor in PDA cells that restricts metastatic behaviors through direct negative regulation of CD44, providing support for the clinical investigation of therapeutic approaches focusing on targeted KLF4 activation in advanced tumors.