The two facets of gp130 signalling in liver tumorigenesis

Schmidt-Arras, Dirk; Galun, Eithan; Rose–John, Stefan

doi:10.1007/s00281-021-00861-0

Cited by 10 publications

(5 citation statements)

References 181 publications

(229 reference statements)

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“…Gp130 expression is upregulated in various types of tumors and non-neoplastic liver diseases ( 39 , 40 ). It can be regulated by multiple factors ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

Wang

Liu

et al. 2023

Croat Med J

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Aim To investigate the effect of the gp130/STAT3-endoplasmic reticulum (ER) stress axis on hepatocyte necroptosis during acute liver injury. Methods ER stress and liver injury in LO2 cells were induced with thapsigargin, and in BALB/c mice with tunicamycin and carbon tetrachloride (CCl 4 ). Glycoprotein 130 (gp130) expression, the degrees of ER stress, and hepatocyte necroptosis were assessed. Results ER stress significantly upregulated gp130 expression in LO2 cells and mouse livers. The silencing of activating transcription factor 6 (ATF6) , but not of ATF4 , increased hepatocyte necroptosis and mitigated gp130 expression in LO2 cells and mice. Gp130 silencing reduced the phosphorylation of CCl 4 -induced signal transducer and activator of transcription 3 (STAT3), and aggravated ER stress, necroptosis, and liver injury in mice. Conclusion ATF6/gp130/STAT3 signaling attenuates necroptosis in hepatocytes through the negative regulation of ER stress during liver injury. Hepatocyte ATF6/gp130/STAT3 signaling may be used as a therapeutic target in acute liver injury.

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“…Gp130 expression is upregulated in various types of tumors and non-neoplastic liver diseases ( 39 , 40 ). It can be regulated by multiple factors ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

Wang

Liu

et al. 2023

Croat Med J

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“…In an inflammation-induced liver cancer mouse model, single-cell RNA sequencing analysis (scRNA-seq) revealed that HCC-CCA may originate from hepatic progenitor cells, whose transformation depends on IL-6 secreted by parenchymal and non-parenchymal liver senescent cells via the IL-6-gp130 pathway [152]. gp130 is a common signal-transducing component of the functional receptor complexes for the IL-6 family of cytokines, which can be expressed on the membrane of hepatic progenitor cells [153]. Senescence-induced IL-6 firstly binds to its soluble receptor, gp80, so that it can gain the affinity to be trans-presented to gp130 receptor.…”

Section: Senescence In Cholangiocarcinoma (Cca)mentioning

confidence: 99%

“…Accordingly, it has been shown that the pharmacological inhibition of IL-6 trans-signaling via the administration of recombinant sgp130Fc increased tumor cell survival, proliferation, and migration, suggesting that IL-6 signaling can be associated with a better CCA prognosis [159]. In a carcinoma of the gallbladder (GBC), a CCA-related cancer, downregulation of the soluble receptor, gp80, positively correlated with an improvement in overall survival [153]. Taken together, these data suggest a crucial role of IL-6 in cholangiocarcinoma development, although it must be clarified whether it mainly exerts pro-tumorigenic or anti-tumorigenic functions.…”

Section: Senescence In Cholangiocarcinoma (Cca)mentioning

confidence: 99%

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

Gazzillo,

Volponi,

Soldani

et al. 2023

Biomedicines

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Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.

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“…It turned out FIGURE 1 | (A) Overview of IL-6 family cytokine receptor complexes. GP130, LIFR, OSMR, and IL-27Rα/WSX-1 are the only receptor subunits of the family that interact with members of the Janus kinase family and are therefore competent for signal transduction (Schmidt-Arras et al, 2021). (B) Trafficking of IL-6 family cytokine receptors.…”

Section: The Interleukin-6 Family Of Cytokinesmentioning

confidence: 99%

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Schmidt-Arras

Rose–John

2021

Front. Cell Dev. Biol.

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Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

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The two facets of gp130 signalling in liver tumorigenesis

Cited by 10 publications

References 181 publications

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

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