Evidence of Active Pro-Fibrotic Response in Blood of Patients with Cirrhosis

Abstract

The role of systemic immunity in the pathogenesis of cirrhosis is not fully understood. Analysis of transcriptomic profiles in blood is an easy approach to obtain a wide picture of immune response at the systemic level. We studied gene expression profiles in blood from thirty cirrhotic patients and compared them against those of eight healthy volunteers. Most of our patients were male [n = 21, 70%] in their middle ages [57.4 ± 6.8 yr]. Alcohol abuse was the most frequent cause of cirrhosis (n = 22, 73%). Eleven patients had hepatocellular carcinoma (36.7%). Eight patients suffered from hepatitis C virus infection (26.7%). We found a signature constituted by 3402 genes which were differentially expressed in patients compared to controls (2802 over-expressed and 600 under-expressed). Evaluation of this signature evidenced the existence of an active pro-fibrotic transcriptomic program in the cirrhotic patients, involving the [extra-cellular matrix (ECM)-receptor interaction] & [TGF-beta signaling] pathways along with the [Cell adhesion molecules] pathway. This program coexists with alterations in pathways participating in [Glycine, serine and threonine metabolism], [Phenylalanine metabolism], [Tyrosine metabolism], [ABC transporters], [Purine metabolism], [Arachidonic acid metabolism]. In consequence, our results evidence the co-existence in blood of a genomic program mediating pro-fibrotic mechanisms and metabolic alterations in advanced cirrhosis. Monitoring expression levels of the genes involved in these programs could be of interest for predicting / monitoring cirrhosis evolution. These genes could constitute therapeutic targets in this disease.

Chronically high level of tgfb1a induction causes both hepatocellular carcinoma and cholangiocarcinoma via a dominant Erk pathway in zebrafish

“…In several independent transcriptomic analyses of NASH, cirrhosis and HCC in human, TGFB1 was consistently up-regulated [ 14 , 23 , 24 ]. However, a lack of coherent study across different stages of the liver disease on TGFb1 expression and its downstream activation hindered the understanding of the chronical effect of TGFB1.…”

A functional variant in TNXB promoter associates with the risk of esophageal squamous‐cell carcinoma

“…Men et al 25 demonstrated that TNXB mapped in pathways of focal adhesion, ECM receptor interaction, and calcium signaling pathway. Sanchez‐Antolín et al 37 previously reported that TNXB affected the activation of the TGF‐β signaling, and TGF‐β could interact with the PI3K‐Akt signaling, potentially 38 . Since the exact role or mechanism of TNXB in ESCC remained largely undiscovered, here, we conducted co‐expression and gene set enrichment analysis using mRNA expression data in ESCC.…”

An estrogen receptor β-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors

“…To confirm the histological findings, we searched for the expression of specific genes that contribute to fibrosis and inflammation (Figure 4 and supplementary table). Col27A1 and Col5A1, two genes belonging to the collagen class and were shown to be increased in cirrhosis, 32 were upregulated in the liver of vehicle-treated HFD-fed mice but not in the b-LGND2-treated HFD-fed mice. On the other hand, expression of inflammatory genes such as CxCl1, which are involved in neutrophil chemoattractant properties, 33 were up-regulated in the liver of vehicle-treated HFDfed mice but not in the b-LGND2-treated HFD-fed mice.…”