ADAMTS12 is a stromal modulator in chronic liver disease.
Bassil DekkyFida AzarDominique BonnierChristine MonseurChiara KalebićEsther ArpignyAlain ColigeVincent LegagneuxNathalie ThéretPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2023)
Adamalysins, a family of metalloproteinases containing a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTSs), belong to the matrisome and play important roles in various biological and pathological processes, such as development, immunity and cancer. Using a liver cancer dataset from the International Cancer Genome Consortium, we developed an extensive in silico screening that identified a cluster of adamalysins co-expressed in livers from patients with hepatocellular carcinoma (HCC). Within this cluster, ADAMTS12 expression was highly associated with recurrence risk and poorly differentiated HCC signatures. We showed that ADAMTS12 was expressed in the stromal cells of the tumor and adjacent fibrotic tissues of HCC patients, and more specifically in activated stellate cells. Using a mouse model of carbon tetrachloride-induced liver injury, we showed that Adamts12 was strongly and transiently expressed after a 24 h acute treatment, and that fibrosis was exacerbated in Adamts12-null mice submitted to carbon tetrachloride-induced chronic liver injury. Using the HSC-derived LX-2 cell line, we showed that silencing of ADAMTS12 resulted in profound changes of the gene expression program. In particular, genes previously reported to be induced upon HSC activation, such as PAI-1, were mostly down-regulated following ADAMTS12 knock-down. The phenotype of these cells was changed to a less differentiated state, showing an altered actin network and decreased nuclear spreading. These phenotypic changes, together with the down-regulation of PAI-1, were offset by TGF-β treatment. The present study thus identifies ADAMTS12 as a modulator of HSC differentiation, and a new player in chronic liver disease.
Keyphrases
- drug induced
- liver injury
- gene expression
- genome wide
- induced apoptosis
- mouse model
- papillary thyroid
- dna methylation
- cell cycle arrest
- newly diagnosed
- high glucose
- transcription factor
- transforming growth factor
- prognostic factors
- ejection fraction
- bone marrow
- diabetic rats
- autism spectrum disorder
- intensive care unit
- respiratory failure
- skeletal muscle
- lymph node metastasis
- epithelial mesenchymal transition
- replacement therapy
- network analysis
- cell migration
- combination therapy
- stress induced