Enhancer of zeste homolog 2-catalysed H3K27 trimethylation plays a key role in acute-on-chronic liver failure via TNF-mediated pathway

Zhou, Tianyu; Sun, Ye; Li, Ming; Ding, Yongsen; Yin, Rongkun; Li, Ziqiang; Xie, Qing; Bao, Shaowen; Cai, Wei

doi:10.1038/s41419-018-0670-2

Cited by 30 publications

(36 citation statements)

References 44 publications

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“…In addition, the classification of IL-36α as either high or low was based on a naked eye scoring system. On the other hand, our quantification was performed objectively using computerised software (ImagePro Plus 9.1), which is routinely used in our research group [21], in addition to the comparison with non-cancer paired colonic tissues. Thus, our rigorous data are probably more convincing and reliable.…”

Section: Discussionmentioning

confidence: 99%

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IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

Chen

Zhang

et al. 2020

BMC Cancer

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Background and aims: Colorectal cancer (CRC) is a major killer. Host immunity is important in tumorigenesis. Direct comparison among IL-36α, IL-36β and IL-36γ in the prognosis of CRC is unclear. Methods: CRC tissue arrays were generated from colorectostomy samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, IL-36α, IL-36β and IL-36γ were determined, in comparison to non-cancer tissues. Results: A significant association was observed between colonic IL-36α, IL-36β or IL-36γ and the presence of cancer (with all P < 0.0001). Using ROC curve analysis, specificity and sensitivity of IL-36α, IL-36β or IL-36γ were confirmed, with area under the curve (AUC) values of 0.68, 0.73 and 0.65, respectively. Significant differences in survival were observed between IL-36α high and IL-36α low (P = 0.003) or IL-36γ high and IL-36γ low (P = 0.03). Survival curves varied significantly when further stratification into subgroups , on the basis of combined levels of expression of two isotypes of IL-36 was undertaken. A significant difference was observed when levels of IL-36α and IL-36β were combined (P = 0.01), or a combination of IL-36α plus IL-36γ (P = 0.002). The subgroups with a combination of IL-36α high plus IL-36β high , or IL-36α high plus IL-36γ low exhibited the longest survival time among CRC patients. In contrast, the subgroups of IL-36α low plus IL-36β high or IL-36α low plus IL-36γ high had the shortest overall survival. Using the log-rank test, IL-36α high expression significantly improved survival in patients with an invasion depth of T4 (P < 0.0001), lymph node metastasis (P = 0.04), TNM III-IV (P = 0.03) or with a right-sided colon tumour (P = 0.02). Similarly, IL-36γ low expression was significantly associated with improved survival in patients with no lymph node metastasis (P = 0.008), TNM I-II (P = 0.03) or with a left-sided colon tumour (P = 0.05). Multivariate analysis demonstrated that among IL-36α, IL-36β and IL-36γ, only IL-36α (HR, 0.37; 95% CI, 0.16-0.87; P = 0.02) was an independent factor in survival, using Cox proportional hazards regression analysis. Conclusion: IL-36α or IL-36γ are reliable biomarkers in predicting the prognosis of CRC during the later or early stages of the disease, respectively. Combining IL-36α plus IL-36γ appears to more accurately predict the postoperative prognosis of CRC patients. Our data may be useful in the management of CRC.

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Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry was performed, as described previously [21]. Briefly, small cores from formalin fixed, wax embedded CRC and non-cancer tissue blocks were embedded in a Tissue Microarray (TAM), as described in detail previously [22].…”

Section: Immunohistochemistrymentioning

confidence: 99%

IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

Chen

Zhang

et al. 2020

BMC Cancer

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“…Because of the predominant nuclear localization of EZH2, and the small percentage of HSCs in liver tissues, specific EZH2 staining of activated HSCs in human samples has been difficult, however, increased global expression of EZH2 has been shown in mice treated with CCL 4 vs controls, 24 and in patients with liver failure and liver cancer as compared with healthy controls. 33 , 34 …”

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis

Martín-Mateos

Assuncao

Arab

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsTransdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways.MethodsWe performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators.ResultsEnhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β–induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β–treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays.ConclusionsTGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β–treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606)

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“…To explore the relationship between NMI and Kupffer cells, double immunofluorescent labeling was applied to determine co‐localization of NMI with CD68 in these human liver tissue, as described . Briefly, the liver sections were incubated with blocking solution at room temperature for 1 h, followed by an overnight incubation at 4°C with the mixture of anti‐NMI antibody (1:100; Abcam) and anti‐CD68 antibody (1:200; Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…To explore the relationship between NMI and Kupffer cells, double immunofluorescent labeling was applied to determine co-localization of NMI with CD68 in these human liver tissue, as described. 15 Briefly, the liver sections were incubated with blocking solution at room temperature for 1 h, followed by an overnight incubation at 4°C with the mixture of anti-NMI antibody (1:100; Abcam) and anti-CD68 antibody (1:200; Abcam). Subsequently, Alexa Fluor 488-conjugated secondary antibody (1:200; Abcam) and Alexa Fluor 555-conjugated secondary antibody (1:200; Invitrogen) were incubated for 1 h at room temperature in the dark, followed by a 5-min incubation of DAPI at room temperature in the dark.…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

N‐myc and STAT interactor correlates with severity and prognosis in acute‐on‐chronic liver failure of hepatitis B virus

Xiong

Zhou

et al. 2019

J of Gastro and Hepatol

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Background and Aim Hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) is characterized by acute deterioration of chronic liver disease with excessive inflammation. N‐myc and STAT interactor (NMI), an inflammation‐mediated protein, involves in various inflammatory‐related diseases, but the role of NMI in development and prognosis in HBV‐ACLF remains to be elucidated. Methods Serum NMI from healthy controls (HCs, n = 20), chronic hepatitis B (CHB, n = 50) patients, and HBV‐ACLF patients (n = 50) was determined using ELISA. NMI from peripheral blood mononuclear cells and liver was confirmed using quantitative real‐time polymerase chain reaction, Western blot, and immunofluorescence. Results Serum NMI was increased 1.9‐fold or 2.2‐fold from HBV‐ACLF patients compared with that from HCs (P < 0.01) or CHB patients (P < 0.01). Consistently, NMI from peripheral blood mononuclear cells was upregulated significantly from HBV‐ACLF patients compared with that from HCs and CHB patients at mRNA and protein levels. Hepatic NMI from HBV‐ACLF patients was 2.8‐fold higher than that from HCs. Serum NMI was correlated with Model for End‐stage Liver Disease, Chronic Liver Failure Consortium ACLF score, and ACLF grades. In contrast, serum NMI was significantly decreased in HBV‐ACLF ameliorated patients during follow‐up, whereas serum NMI was sustained at high levels in non‐ameliorated patients. Elevated serum NMI (≥ 198.5 pg/mL) was correlated with poor survival rate of HBV‐ACLF patients. Using receiver operating characteristics curves, it was suggested that serum NMI was a potential biomarker in predicting 3‐month mortality of HBV‐ACLF patients. Conclusions Our study highlights the potential role of NMI in assessing the development and prognosis of HBV‐ACLF.

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Enhancer of zeste homolog 2-catalysed H3K27 trimethylation plays a key role in acute-on-chronic liver failure via TNF-mediated pathway

Cited by 30 publications

References 44 publications

IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis

N‐myc and STAT interactor correlates with severity and prognosis in acute‐on‐chronic liver failure of hepatitis B virus

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