ADAMTS12 is a stromal modulator in chronic liver disease

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. ADAMTS12 expression is linked to recurrence risk in patients with hepatocellular carcinoma. ADAMTS12 is expressed by stromal cells both in tumors and fibrosis adjacent to tumors. In mice, Adamts12 expression is transiently induced after acute liver injury along with inflammation markers. Adamts12 invalidation affects the response to liver injury and exacerbates fibrosis. Cultured hepatic stellate cells (HSC) express ADAMTS12 and silencing ADAMTS12 leads to down‐regulation of genes expressed in activated HSCs, with features evocative of an intermediate and reactivatable state.