Low ECM1 expression temporally promote proliferative, tumorigenic and inflammatory gene signatures in mouse liver

Y Li; T Itze; C Meyer; MP Ebert; A Teufel; W Fan; NJ Török; Z Nwosu; S Dooley

doi:10.1055/s-0040-1721974

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2021; 59(01): e12
DOI: 10.1055/s-0040-1721974

Poster Visit Session I Basic Hepatology (Fibrogenesis, NPC, Transport)

Friday, January 29, 2021, 12:30 pm – 1:15 pm, Poster Session Virtual Venue

Low ECM1 expression temporally promote proliferative, tumorigenic and inflammatory gene signatures in mouse liver

Authors

Y Li

¹Medical Faculty Mannheim, Heidelberg University, Sektion Molecular Hepatology, Dept. of Medicine II, Mannheim, Germany
T Itze

²Medical Faculty Mannheim, Heidelberg University, Dept. of Medicine II, Mannheim, Germany
C Meyer

¹Medical Faculty Mannheim, Heidelberg University, Sektion Molecular Hepatology, Dept. of Medicine II, Mannheim, Germany
MP Ebert

²Medical Faculty Mannheim, Heidelberg University, Dept. of Medicine II, Mannheim, Germany
A Teufel

²Medical Faculty Mannheim, Heidelberg University, Dept. of Medicine II, Mannheim, Germany
W Fan

³Stanford University School of Medicine, Department of Gastroenterology and Hepatology, San Francisco, United States
NJ Török

³Stanford University School of Medicine, Department of Gastroenterology and Hepatology, San Francisco, United States
Z Nwosu

⁴Rogel Cancer Center, University of Michigan, Department of Molecular and Integrative Physiology, Ann Arbor, United States
S Dooley

¹Medical Faculty Mannheim, Heidelberg University, Sektion Molecular Hepatology, Dept. of Medicine II, Mannheim, Germany

Abstract

Full Text

Background We recently provided the first evidence that ECM1 (extracellular matrix protein 1) plays a crucial role in liver homeostasis by attenuating TGF-β activation. ECM1 is often downregulated in liver diseases, including liver cancer and non-alcoholic fatty liver disease. Here we examined the dynamic genomic profile of ECM1 knockout mice liver to define the global molecular changes accompanying its expression depletion.

Methods RNA sequencing was performed in ECM1KO mice aged 2, 5 and 8 weeks, representing the initial, intermediate, and advanced phases of the liver disease, respectively. This was accompanied by differentially expressed genes identification and pathway enrichment analysis. Further, to interrogate the link to fibrosis, ECM1 gene expression changes were compared to that derived from activated hepatic stellate cells.

Results ECM1 maintains homeostasis in healthy liver architecture and function. Depletion of ECM1 in mice disturbes liver architecture and causes death at about 8 weeks due to liver failure. There were ~ 2x more differentially expressed genes at the early time point (2 weeks) than at the later (8 weeks) time point, suggesting that most alterations were initiated at the early stage. Livers of ECM1KO mice generally showed a notable downregulation of metabolic pathways, and a high expression of cell cycle, proliferation, focal adhesion and PI3K-Akt pathways. While fibrosis signatures persisted from early to the late stage, genes driving pathways in cancer, including hippo, Wnt signaling and ECM-receptor interaction were upregulated at 2 weeks, whereas inflammatory signatures including cytokine-cytokine receptor interaction, chemokine signaling pathway, TNF signaling and Toll-like receptor interaction were the predominant alterations at the 8 weeks time point.

Conclusion Our data suggest that ECM1 suppression temporary provokes tumorigenic signatures at the onset of liver disease and lead to profound inflammatory changes as the disease progresses. These findings pave the way for the characterization of early and late stage signatures driving the initiation and maintenance of liver diseases.