Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases

Liu, Ting; Zhou, Yu; Ko, Kwang Suk; Yang, Heping

doi:10.1155/2015/276850

Cited by 58 publications

(54 citation statements)

References 136 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CLD can be triggered by numerous factors including diet, alcohol, viral infection and genetic disorders, which share common features including excessive inflammation 2 , dysregulated transforming growth factor (TGFβ) signalling 3 and dramatic disruption in the vascular architecture of the liver 4, 5 . Recent studies have revealed that disruption of endothelial cell (EC) homoeostasis can initiate tissue damage and fibrosis 6–8 .…”

Section: Introductionmentioning

confidence: 99%

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

et al. 2017

View full text Add to dashboard Cite

The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (Erg cEC-Het) and inducible homozygous deficient mice (Erg iEC-KO), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Our results are consistent with previous findings reporting that IL-8 and IL-1β are targets of β-catenin 28,29 and c-myc. 30,31 Interestingly, IL-8-KO and IL-1β-KO IC clones, characterized by nearly undetectable levels of cytokines mRNA (Figs. 6b and 6c) and protein (Figs.…”

Section: The Gsk3β/β-catenin/c-myc Axis Upregulates Abcb5 In Mpm Icsmentioning

confidence: 99%

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Milosevic

Kopecka

Salaroglio

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM‐initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness‐related pathways determine chemoresistance. Moreover, there are no predictive markers of IC‐associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness‐related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo‐sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5‐knocked‐out (KO) IC clones were resensitized to the drugs in vitro and in patient‐derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β‐catenin/c‐myc axis that also increased IL‐8 and IL‐1β production. IL‐8 and IL‐1β‐KO IC clones reduced the c‐myc‐driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5‐KO clones had lower IL‐8 and IL‐1β secretion, and c‐myc transcriptional activity, suggesting that either Wnt/GSK3β/β‐catenin and IL‐8/IL‐1β signaling drive c‐myc‐mediated transcription of ABCB5. ABCB5 correlated with lower time‐to‐progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first‐line chemotherapy in MPM patients.

show abstract

“…Zhang et al found that the TF E2F1 was a new profibrotic factor that could facilitate the progression of liver fibrosis through the Egr-1/SHP/EID1 network[17]. MYC promotes the progression of liver cirrhosis by upregulating the inflammatory factors IL8, IL10, and TGFβ[18]. All of these previous reports were validated in our TF—miRNA—mRNA network.…”

Section: Discussionmentioning

confidence: 56%

Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis

et al. 2017

View full text Add to dashboard Cite

Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including “immune response” as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma.

show abstract

Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases

Cited by 58 publications

References 136 publications

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis

Contact Info

Product

Resources

About