Up-Regulation of Kruppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α
Up-Regulation of Kruppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α
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DOI：
10.1158/1541-7786.mcr-08-0525
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发表时间：
2009-08-01
影响因子：
5.2
通讯作者：
Stoeltzing, Oliver
中科院分区：
文献类型：
--
作者：
Mori, Akira;Moser, Christian;Stoeltzing, Oliver
Kruppel-like factor 5 （KLF5）是一种参与细胞转化、增殖和癌变的转录因子，可通过RAS突变上调。然而，关于它是作为肿瘤抑制因子还是作为致癌基因，争论仍然存在。由于KRAS在胰腺癌中经常发生突变，我们研究了KLF5在这种癌症实体中的调控作用。我们的研究结果表明，KLF5在胰腺癌细胞中过表达，并且超过了kras突变的结肠癌细胞的KLF5表达。令人惊讶的是，抑制B-Raf/C-Raf或MAPK/Erk并没有降低KLF5水平，这表明KRAS-Raf-MEK-Erk信号在胰腺癌中并没有促进KLF5的表达。这一发现与mek - erk介导的KLF5诱导结肠癌细胞的报道形成鲜明对比。此外，在胰腺癌细胞中，KLF5的表达水平与KRAS的突变状态和MEK的磷酸化无关。重要的是，KLF5在白细胞介素(IL)-1 β或缺氧的情况下显著上调。IL-1 β介导的KLF5诱导通过阻断p38通路而减弱。此外，阻断IL-1R可降低组成型KLF5的表达，提示存在自分泌激活环。此外，KLF5与缺氧诱导因子-la （HIF-1 α）和HIF-1 α (siRNA)共免疫沉淀可降低组成型KLF5。同样，KLF5（siRNA）降低了HIF-1a靶基因GLUT-1的表达。此外，高细胞密度、非锚定细胞生长和肿瘤球体中KLF5的表达显著升高。RNA对KLF5的下调减少的表达
Kruppel-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)-1 beta or hypoxia. The IL-1 beta-medlated 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-la (HIF-1 alpha) and HIF-1 alpha(siRNA) reduced constitutive KLF5. Similarly, KLF5(siRNA) reduced the expression of the HIF-1a 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 RNA! reduced the expression of