Dataset Information

Transforming Growth Factor-? and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma.

ABSTRACT: Transforming growth factor (TGF)-? suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-? switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-?. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF-? stimulation, although they exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-?. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-? expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression, suggesting that CXCL5 is a TGF-? target gene collaborating with Axl signaling. Loss of either TGF-? or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue, and reduced survival. Conclusion: The synergy of TGF-? and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. Intervention with TGF-?/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGF-?-positive patients.

SUBMITTER: Haider C

PROVIDER: S-EPMC6590451 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Transforming Growth Factor-β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma.

Haider Christine C Hnat Julia J Wagner Roland R Huber Heidemarie H Timelthaler Gerald G Grubinger Markus M Coulouarn Cédric C Schreiner Wolfgang W Schlangen Karin K Sieghart Wolfgang W Peck-Radosavljevic Markus M Mikulits Wolfgang W

Hepatology (Baltimore, Md.) 20181220 1

Transforming growth factor (TGF)-β suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-β switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-β. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF-β stimulation, although they exhib ...[more]

PMID: 30014484

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Project description:Hepatocellular carcinoma (HCC) is often associated with an inflammatory setting. A plethora of cytokines are secreted in this milieu, actively contributing to the progression of the disease; however, the extent of cytokine interaction and how it contributes to HCC development remains an enigma. In this regard, our analysis of available patient-derived data suggests that cytokines like interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) are enriched in HCC. We further analyzed the effect of these cytokines independently or in combination on HCC cells. Importantly, IL-6 was found to induce a STAT-3-dependent proliferation and mediate its pro-proliferative effects through activation and direct interaction with the p65 subunit of NFkB. Alternatively, TGF-β was found to induce a SMAD-dependent induction of epithelial to mesenchymal transition (EMT) coupled to growth arrest in these cells. Interestingly, the simultaneous addition of IL-6 and TGF-β failed to profoundly impact EMT markers but resulted in attenuation of IL-6-induced pro-proliferative effects. Analysis of the putative molecular mechanism revealed a decrease in IL-6 receptor (IL-6R) transcript levels, reduced expression of IL-6-induced STAT-3, and its nuclear localization upon addition of TGF-β along with IL-6. Consequently, a reduced p65 activation was also observed in combination treatment. Importantly, SMAD levels were unperturbed and the cells showed more TGF-β-like features under combination treatment. Finally, we observed that TGF-β resulted in enrichment of repressive chromatin mark (H3K27me3) coupled to growth arrest, while IL-6 induced an open chromatin signature (H3K4me3) associated with an enhanced expression of EZH2. Overall, for the first time, we show that TGF-β attenuates IL-6-induced effects by regulating the receptor level, downstream signaling, and the epigenome. Understanding the complex interactions between these cytokines can be imperative to a better understanding of the disease, and manipulation of cytokine balance can act as a prospective future therapeutic strategy.

Dataset Information

Transforming Growth Factor-? and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma.

Publications

Transforming Growth Factor-β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma.

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