KLF4-mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis

KLF4 and CD44 promote 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.

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