Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma

Yi, Peng; Shu, Yan; Bi, Wang; Zheng, Xiang; Feng, Weixi; He, Lin; Li, Jian Shui

doi:10.1002/jcp.28877

Cited by 11 publications

(12 citation statements)

References 55 publications

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“…Among all of the upregulated genes, several stand out as possible mediators of entolimod's tissue protective activity in the liver. For example, the tissue protective TNFAIP3 (A20) protein was previously shown to specifically reduce TNF toxicity and protect the liver and endothelial cells from apoptosis [50,51] and was strongly induced by entolimod in both our liver and hepatocyte experiments (10.42-fold and 7.15-fold, respectively), but was not upregulated in livers after LPS treatment. Another gene found to be strongly upregulated by entolimod in our study is RCAN1 (regulator of calcineurin 1), which was previously shown to preserve endothelial integrity and reduce vascular barrier breakdown by increasing resistance to damaging systemic anaphylaxis [52].…”

Section: Pro-survival Transcriptional Response To Entolimod In the Mumentioning

confidence: 79%

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

et al. 2020

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Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS-and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.

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Section: Pro-survival Transcriptional Response To Entolimod In the Mumentioning

confidence: 79%

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

et al. 2020

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“…Our results highlight the important role of proinflammatory mechanism mediated by RIPK1 in promoting liver fibrosis and HCC formation, largely independent of cell death and compensatory proliferation. In this regard, it is interesting to note that down-regulation of A20, an important suppressor of RIPK1 and the NF-κB pathway, has been associated with invasiveness of human HCCs and reduced disease-free survival (62). Mutant mice with A20 knockout specifically in liver parenchymal cells spontaneously develop chronic liver inflammation but no fibrosis or HCCs (63).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Tan

Zhao

Cao

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 inTak1ΔHEPmice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation inTak1ΔHEPmice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

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“…Low expression of TNFAIP3 was also found in pancreatic cancer tissues 35 . Studies on liver tumor development indicated that TNFAIP3 plays an important role in liver protection and tumor prevention, by limiting chronic liver in ammation, stimulating hepatocyte growth, inhibiting the activation of protein tyrosine kinase 2 and Rac family GTPase 1, and preventing epithelial-mesenchymal transition 36,37 . Based on the expression pro le analysis of TNFAIP3 in TCGA database and lung tumor tissue microarray, we hypothesized that TNFAIP3 plays the role of tumor suppressor in lung tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

Chen

Gao²,

et al. 2020

Preprint

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Background: The ubiquitin-editing enzyme TNF inducible protein 3 (TNFAIP3) is a crucial regulator of inflammation and immunity. It is also involved in tumorigenesis of various cancers such as lymphomas, colorectal tumors and breast cancer. In this study, we aimed to explore the role and regulatory mechanism of TNFAIP3 in lung cancer. Methods: The expression of TNFAIP3 was determined in the Cancer Genome Atlas (TCGA) database. The levels of TNFAIP3 in lung cancer tissues was determined by immunohistochemistry (IHC) assay. TNFAIP3 knockdown and overexpression were performed, followed by further evaluation of cell viability, cell cycle and apoptosis. Cell cycle and apoptosis were observed by using flow cytometry and the key regulatory proteins were detected by western blotting. Colony formation assessment and EdU assay were adopted to check cell proliferation. Results: TNFAIP3 expression was downregulated in lung cancer tissues at both mRNA and protein levels, comparing with that in adjacent non-tumor tissues. Consequently, the colony formation ability of lung cancer cells was enhanced, and the number of EdU positive lung cancer cells was increased. By contrast, elevated TNFAIP3 expression resulted in decreased colony formation ability of lung cancer cells. Mechanistically, TNFAIP3 overexpression rendered cell cycle of lung cancer cells halted at G0/G1 phase and caused apoptosis of lung cancer cells.Conclusion: Our data suggested that TNFAIP3 exhibits tumor suppressive roles in lung cancer.

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Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma

Abstract: Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is a major public health problem. Zinc finger protein A20

Cited by 11 publications

References 55 publications

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

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Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma

Abstract: Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is a major public health problem. Zinc finger protein A20

Cited by 11 publications

References 55 publications

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects

Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

TNFAIP3&nbsp;Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

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TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis