Downregulation of ECM1 in hepatocytes as a damage response to liver injury

Background Liver disease progression depends on dynamic cell-cell communication among hepatic cells. Upon hepatocytes injury, HSCs are activated and differentiate into myofibroblast-like cells, in which TGF-β plays a crucial role. In healthy liver, latent TGF-β is stored in extracellular matrix and kept quiescent by ECM1. Upon damage, ECM1 production is downregulated in hepatocytes leading to L-TGF-β activation to initiate fibrosis. The mechanism of ECM1 expression regulation is not clear yet.

Methods In silico promoter analysis and correlative datasets were used to predict pathways relevant for ECM1 regulation. Functional assays were done in HCC cell lines, AML12, mouse and human primary hepatocytes, and in mice.

Results In acute PHx and CCl4 models, ECM1 is reduced in early stages of damage/regeneration, accompanied by enhanced TGF-β signaling. ECM1 is consistently downregulated in human HCC datasets and HCC cell lines. In silico analysis gives us potential transcriptional factors. Along this line, EGF and HGF promote ECM1 expression in vitro, and downstream signaling inhibitors suggest involvement of MEK-ERK pathway. At the transcription factor level, STAT1KD decreases ECM1 expression. Furthermore, YAP activation frequently accompanies low ECM1 expression levels. Injection of EGF to WT mice does not induce ECM1 expression above homeostatic levels, suggesting that EGFR/c-MET might be the rate-limiting components. Indeed, EGFR is downregulated in the PHx model in parallel to the decrease of ECM1 expression.

Conclusion ECM1 downregulation is a robust biomarker of chronic liver disease progression and acute liver damage, and can be developed as a therapeutic target, which warrants more detailed mechanistic evaluation.

 

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Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022