Cross-talk between Aryl Hydrocarbon Receptor and Mitogen-Activated Protein Kinase Signaling Pathway in Liver Cancer through c-raf Transcriptional Regulation

Borlak, Jürgen; Jenke, Hans Stephan

doi:10.1158/1541-7786.mcr-08-0042

Cited by 18 publications

(10 citation statements)

References 45 publications

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“…The mechanism underlying the LPS-induced cross-talk between Ahr and Sp1, however, remains to be investigated in detail. Recent studies have demonstrated cross-talk between the Ahr signaling pathway and MAP kinase pathways (43,44). As MAPKs have been shown to play an important role in Sp1 activation downstream of LPS signaling (45), these reports lead us to hypothesize that the cross-talk between Sp1 and Ahr may be mediated by MAPK activation.…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages

Masuda

Kimura

Hanieh

et al. 2011

International Immunology

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Macrophages play a pivotal role in innate immune responses to pathogens via toll-like receptors. We previously demonstrated that aryl hydrocarbon receptor (Ahr) in combination with signal transducer and activator of transcription 1 (Stat1) negatively regulates pro-inflammatory cytokine production by inhibiting nuclear factor-κB activation in macrophages after LPS stimulation. Here, we show that Ahr also negatively regulates production of the pro-inflammatory cytokine IL-6 by suppressing histamine production in macrophages stimulated by LPS. We found that Ahr-Sp1 complex, independent of Stat1, represses histidine decarboxylase expression by inhibiting LPS-induced Sp1 phosphorylation on Ser residues in macrophages; this leads to suppression of histamine production. Moreover, we found that loratadine and chlorpromazine, histamine 1 receptor (H1R) antagonists, more effectively impair the production of LPS-induced IL-6 than that of other inflammatory cytokines in Ahr(-/-) macrophages. Collectively, these results demonstrate that Ahr negatively regulates IL-6 production via H1R signaling through the suppression of histamine production in macrophages following LPS stimulation.

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Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages

Masuda

Kimura

Hanieh

et al. 2011

International Immunology

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“…Disruption of the cellular functions of AHR is also associated with the expression of various diseases, including HCC [25]. The underlying regulatory mechanisms of tumorigenesis remain unclear.…”

Section: Resultsmentioning

confidence: 99%

Aryl hydrocarbon receptor regulates histone deacetylase 8 expression to repress tumor suppressive activity in hepatocellular carcinoma

et al. 2016

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Histone deacetylase 8 (HDAC8), a unique member of class I histone deacetylases, shows remarkable correlation with advanced disease stage and multiple malignant tumors However, little is known about the contribution of HDAC8 to the tumorigenesis of hepatocellular carcinoma (HCC). The present study investigated the expression of HDAC8 regulated by the aryl hydrocarbon receptor (AHR) in HCC cell lines and tissues, and the roles of HDAC8 overexpression in cell proliferation, including potentially underlying mechanisms. We assessed the correlation between the clinic-pathological parameters and the expression of AHR and HDAC8. Further, we analyzed the AHR siRNA transfection and HDAC8 inhibitors to explore the functions of HDAC8 in HCC progression in vitro and in vivo. In a panel of 289 HCC patients, HDAC8 was shown to be highly correlated with AHR expression at both mRNA and protein levels. HCC patients with high AHR expression showed a shorter survival time than that with low AHR expression. We then found that the expression of both AHR and HDAC8 was significantly upregulated in both HCC cell lines and tumor tissues compared to human normal hepatocytes and matched non-tumor tissues. Furthermore, HDAC8 inhibition remarkably inhibited hepatoma cell proliferation and transformation activity via upregulation of RB1 in vitro and in vivo. Our data revealed an important role of the AHR-HDAC8 axis in promoting HCC tumorigenesis, thus identifying HDAC8 as a potential therapeutic target for HCC treatment.

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“…The most significantly enriched canonical pathway was the Aryl Hydrocarbon Receptor Signaling pathway (AHR pathway, p < 3.0 × 10 −6 ), which belongs to the basic helix-loop-helix/Per-Arnt-Sim family of transcription factors (Figure 2 B). This pathway has been reported to regulate xenobiotic metabolizing enzymes such as cytochrome P450 and has been demonstrated to cross-talk with the MAPK pathway [ 25 , 26 ]. Recent studies revealed that the AHR pathway is involved in various signaling pathways that are critical to cell proliferation and differentiation, gene regulation, cell motility and migration, and inflammation [ 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAF V600E in melanoma

Zhao

2015

Mol Cancer

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BackgroundThe recurrent BRAF driver mutation V600E (BRAFV600E) is currently one of the most clinically relevant mutations in melanoma. However, the genome-wide transcriptional and epigenetic dysregulations induced by BRAFV600E are still unclear. The investigation of this driver mutation’s functional consequences is critical to the understanding of tumorigenesis and the development of therapeutic strategies.Methods and resultsWe performed an integrative analysis of transcriptomic and epigenomic changes disturbed by BRAFV600E by comparing the gene expression and methylation profiles of 34 primary cutaneous melanoma tumors harboring BRAFV600E with those of 27 BRAFWT samples available from The Cancer Genome Atlas (TCGA). A total of 711 significantly differentially expressed genes were identified as putative BRAFV600E target genes. Functional enrichment analyses revealed the transcription factor MITF (p < 3.6 × 10−16) and growth factor TGFB1 (p < 3.1 × 10−9) were the most significantly enriched up-regulators, with MITF being significantly up-regulated, whereas TGFB1 was significantly down-regulated in BRAFV600E, suggesting that they may mediate tumorigenesis driven by BRAFV600E. Further investigation using the MITF ChIP-Seq data confirmed that BRAFV600E led to an overall increased level of gene expression for the MITF targets. Furthermore, DNA methylation analysis revealed a global DNA methylation loss in BRAFV600E relative to BRAFWT. This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAFV600E. Finally, we demonstrated that BRAFV600E targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.ConclusionsOur integrative analysis identified a set of BRAFV600E target genes. Further analyses suggested a complex mechanism driven by mutation BRAFV600E on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0328-y) contains supplementary material, which is available to authorized users.

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Cross-talk between Aryl Hydrocarbon Receptor and Mitogen-Activated Protein Kinase Signaling Pathway in Liver Cancer through c-raf Transcriptional Regulation

Abstract: c-raf is a serine-threonine kinase and a downstream effector of ras signaling.

Cited by 18 publications

References 45 publications

Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages

Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages

Aryl hydrocarbon receptor regulates histone deacetylase 8 expression to repress tumor suppressive activity in hepatocellular carcinoma

In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAF V600E in melanoma

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