Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori, Akira; Moser, Christian; Lang, Sven A.; Hackl, Christina; Gottfried, Eva; Kreutz, Marina; Schlitt, Hans J.; Geissler, Edward K.; Stoeltzing, Oliver

doi:10.1158/1541-7786.mcr-08-0525

Cited by 66 publications

(46 citation statements)

References 42 publications

(55 reference statements)

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“…Besides, mediates Cyclin D1 expression and cell proliferation via interaction with c-Jun in vascular smooth muscle cells [22]. Therefore, our results together with these reports demonstrate that KLF5 may play an oncogenic role to promote cell proliferation and tumor development [19,20]. However, recent studies also suggest that expression of KLF5 is severely lost in human esophageal squamous cell cancer (ESCC) [23,24].…”

Section: Discussionsupporting

confidence: 52%

“…In tumors, levels of KLF5 expression increased in parallel with advancing stages of neoplastic progression in patients with gastric cancer [19]. Besides, up-regulation of Krüppel-like factor 5 was also observed in pancreatic cancer due to interleukin-1beta signaling and hypoxia-inducible factor-1alpha [20]. However, its roles in lung carcinoma remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Krüppel-Like Factor 5 Promotes Lung Tumorigenesis through Upregulation of Sox4

Zhao²,

Zhou

et al. 2014

Cell Physiol Biochem

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Background: Krüppel-like factor 5 (KLF5), a member of zinc finger class of DNA-binding transcriptional regulators, has attracted attention because of its important regulatory activities linked to diverse functions such as cell growth, proliferation, differentiation, apoptosis and tumorigenesis in a number of systems. However, its biological functions in the initiation and progression of lung tumorigenesis remain largely unexplored. Methods: Quantitative realtime PCR and Western Blot were used to detect the expression of KLF5 in lung cancer tissues and cell lines. Retro-viruses were used to generate KLF5 stable expression lung cancer cell line. Small interfering RNA was used to silence the expression of KLF5 and Sox4. BrdU assay was used to determine the proliferation of cells. Luciferase and Chromatin immunoprecipitation assays were used to detect the regulation of Sox4 by KLF5. Results: KLF5 was up-regulated in lung cancer tissues and cell lines. Overexpression of KLF5 promotes while knockdown of its expression inhibits cell proliferation in two cell lines derived from lung carcinoma. At the molecular level, our results revealed that KLF5 positively regulates Sox4 expression through a transcriptional mechanism. Sox4 deficiency blocked the proliferative roles of KLF5 in lung cancer cells. Conclusion: our data identified the KLF5/Sox4 regulatory signaling play an important role in lung tumorigenesis, which might represent novel therapeutic targets to manage lung carcinoma.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Krüppel-Like Factor 5 Promotes Lung Tumorigenesis through Upregulation of Sox4

Zhao²,

Zhou

et al. 2014

Cell Physiol Biochem

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“…The Fbw7 heterozygous knockout mice increase susceptibility to radiation-induced tumorigenesis (6). It is well documented that KLF5 plays oncogenic roles in breast cancer (17), colon cancer (35), leukemia (36), and pancreatic cancer (37). These findings suggest that genetic inactivation of Fbw7 in a variety of cancers could promote cancer progression through accumulating KLF5.…”

Section: Discussionmentioning

confidence: 98%

The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation

Zhao

Zheng²,

Zhou³

et al. 2010

Cancer Research

131

145

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Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes breast cell proliferation and tumorigenesis through upregulating FGF-BP. The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF Fbw7 ) targets KLF5 for ubiquitin-mediated degradation in a GSK3β-mediated KLF5 phosphorylationdependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ( 303 SPPSS)abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and breast cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers. Cancer Res; 70(11); 4728-38. ©2010 AACR.

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“…36,37 IL-1a promotes proliferation, adhesion, and migration in pancreatic cancer cell lines, associating with the activation of Ras and the downstream ERK signaling pathway. 38 Another study demonstrated that IL-1a activates the NF-kB signaling pathway and up-regulates several anti-apoptotic genes, that for Bcl-xL and BfL-1 39 . TGF-b upregulates matrix metalloproteinase 2 (MMP-2) and the urokinase-type plasminogen activator (uPA) system and consequently mediates invasive behavior.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

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Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Cited by 66 publications

References 42 publications

Krüppel-Like Factor 5 Promotes Lung Tumorigenesis through Upregulation of Sox4

Krüppel-Like Factor 5 Promotes Lung Tumorigenesis through Upregulation of Sox4

The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

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