Abstract
Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1beta or hypoxia. The IL-1 beta-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-1alpha(siRNA) reduced constitutive KLF5. Similarly, KLF5(siRNA) reduced the expression of the HIF-1alpha target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/MAPK/Erk signaling, but involves the IL-1beta/IL-1R system, p38, and the transcription factor HIF-1alpha.
Highlights
Pancreatic cancer represents a highly aggressive cancer entity that requires the development of novel targeted therapy concepts to improve overall outcome
Our results show that, at a similar cell density, Krüppellike factor 5 (KLF5) is overexpressed in pancreatic cancer cell lines and, exceeds the KLF5 expression levels of HCT116 colon cancer cells, suggesting that KRAS may play a pivotal role in mediating KLF5 in pancreatic cancer (Fig. 1A and B)
We identified the IL1β/IL-1 receptor (IL-1R) system and the transcription factor hypoxia-inducible factor-1α (HIF-1α), which complexes with KLF5, as mediators of KLF5 induction in this cancer entity
Summary
Pancreatic cancer represents a highly aggressive cancer entity that requires the development of novel targeted therapy concepts to improve overall outcome. Krüppellike factor 5 (KLF5), a zinc finger transcription factor, has been shown to be involved in tumor progression, cell transformation, and angiogenesis [1,2,3,4]. This transcription factor is known as an intestinal-enriched Krüppel-like factor and is predominantly present in the proliferating crypt epithelial cells of the intestine [5]. The biological function of KLF5 elicits some relevant discrepancy among various cancer entities, requiring additional efforts for defining the role of KLF5 in certain malignancies
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