IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice

Bergmann, Juri; Müller, Miryam; Baumann, Niklas; Reichert, Manuel; Heneweer, Carola; Bolik, Julia; Lücke, Karsten; Gruber, Sabine; Carambia, Antonella; Boretius, Susann; Leuschner, Ivo; Becker, Thomas; Rabe, Björn; Herkel, Johannes; Wunderlich, Frank; Mittrücker, Hans‐Willi; Rose–John, Stefan; Schmidt-Arras, D

doi:10.1002/hep.28874

Cited by 141 publications

(130 citation statements)

References 41 publications

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“…We analyzed the microarray data to identify the downstream targets responsible for the biological functions of hPCL3s (Supplementary Table S3). The expression of IL6, which was previously shown to be a driver of HCC (20), was dramatically upregulated upon hPCL3s overexpression in PVTT cells. Consistent with the microarray data, the forced expression of hPCL3s in Hep3B and PVTT cells increased the expression of the IL6 mRNA, whereas hPCL3s knockdown decreased the expression of the IL6 mRNA in PVTT and Huh7 cells ( Fig.…”

Section: Il6 Was a Target Gene Downstream Of Hpcl3s/b-catenin/tcf Sigmentioning

confidence: 79%

hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling

et al. 2018

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Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2), with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has, however, not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic β-catenin destruction complex, inhibited β-catenin degradation, and activated β-catenin/T-cell factor signaling. Downstream of the β-catenin cascade, IL6 mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the β-catenin/IL6 pathway. hPCL3s has an oncogenic role in hepatocellular carcinoma by activating the β-catenin/IL6 signaling axis to promote metastasis. .

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Section: Il6 Was a Target Gene Downstream Of Hpcl3s/b-catenin/tcf Sigmentioning

confidence: 79%

hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling

et al. 2018

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“…Proinflammatory cytokine IL-6 is a primary cytokine in the tumor microenvironment, which is produced by macrophages, neutrophils, monocytes, tumor cells and other cell types [38][39][40]. IL-6 has been demonstrated to promote the invasion of blood vessels by cancer cells through its role as an important trigger of EMT [41].…”

Section: Discussionmentioning

confidence: 99%

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

Yang

et al. 2020

J. Cancer

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Objectives: Aldehyde dehydrogenase 3A1 (ALDH3A1) is a member of the ALDH superfamily and its relationship with oral squamous cell carcinoma (OSCC) still unknown. In our subject, we aimed to reveal the expression pattern and clinical value of ALDH3A1 in OSCC and its biological function in OSCC cell lines. Materials and methods: The expression level of ALDH3A1 in paired OSCC tissues and adjacent noncancerous tissues were detected by quantitative real-time PCR, Western blot and immunohistochemistry. The relationship between ALDH3A1 expression and clinical characteristics was analyzed. Besides, cell-counting kit 8, colony formation, wound healing, transwell invasion, apoptosis and cell cycle assays were employed to assess the role of ALDH3A1 in OSCC cells. To explore the influence of ALDH3A1 on OSCC epithelial-to-mesenchymal transition (EMT), the expression of EMT markers (E-cadherin, vimentin, snail, MMP3) on OSCC cells were detected, and possible mechanisms were analyzed. Results: In OSCC tissues, ALDH3A1 was significantly decreased compared to the adjacent normal tissues. Lower ALDH3A1 expression in OSCC tissues was associated with a higher incidence of lymph node metastasis (LNM). Moreover, the overall survival of OSCC with low ALDH3A1 expression was significantly worse compared to that of OSCC with high ALDH3A1 expression. Restored expression of ALDH3A1 suppressed cell proliferation, migration and invasion in OSCC cells. Further experiments showed that ALDH3A1 might inhibit EMT in OSCC via a regulation of the IL-6/STAT3 signal pathway. Conclusion: These data indicate that ALDH3A1 may serve as a biomarker and may be developed into a novel treatment for OSCC.

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“…Here, we found that increased activity of meprin β on the cell surface reduced cell proliferation. Another pathway influenced by ADAM17, emerging in different tumor entities, is interleukin 6 (IL-6) and IL-6R-induced trans-signaling (Bergmann et al, 2017;Schmidt et al, 2018). Here, ADAM17 releases the IL-6R from the cell surface of one cell, and then this soluble receptor forms a signaling complex together with its cytokine and gp130 (also known as IL6ST) on another cell to induce cell survival via STAT3 phosphorylation (Schaper and Rose-John, 2015).…”

Section: Discussionmentioning

confidence: 99%

The cancer-associated meprin β variant G32R provides an additional activation site and promotes cancer cell invasion

Schäffler¹,

Li²,

Helm³

et al. 2019

Journal of Cell Science

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The extracellular metalloprotease meprin β is expressed as a homodimer and is primarily membrane bound. Meprin β can be released from the cell surface by its known sheddases ADAM10 and ADAM17. Activation of pro-meprin β at the cell surface prevents its shedding, thereby stabilizing its proteolytic activity at the plasma membrane. We show that a single amino acid exchange variant (G32R) of meprin β, identified in endometrium cancer, is more active against a peptide substrate and the IL-6 receptor than wild-type meprin β. We demonstrate that the change to an arginine residue at position 32 represents an additional activation site used by furin-like proteases in the Golgi, which consequently leads to reduced shedding by ADAM17. We investigated this meprin β G32R variant to assess cell proliferation, invasion through a collagen IV matrix and outgrowth from tumor spheroids. We found that increased meprin β G32R activity at the cell surface reduces cell proliferation, but increases cell invasion.

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IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice

Cited by 141 publications

References 41 publications

hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling

hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

The cancer-associated meprin β variant G32R provides an additional activation site and promotes cancer cell invasion

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