University of Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Rennes, France.
Laboratory of Connective Tissues Biology, GIGA-R, University of Liege, Liege, Belgium.
FASEB J. 2023 Nov;37(11):e23237. doi: 10.1096/fj.202200692RRRR.
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.
adamalysins 是一类包含金属蛋白酶、解整合素和金属蛋白酶（ADAMs）和含有血小板反应蛋白基序的 ADAMs（ADAMTSs）的金属蛋白酶家族，属于基质体，在各种生物学和病理过程中发挥重要作用，如发育、免疫和癌症。我们使用国际癌症基因组联盟的肝癌数据集，进行了广泛的计算机筛选，鉴定了一组在肝癌患者肝脏中共同表达的 adamalysins。在这个簇中，ADAMTS12 的表达与复发风险和低分化 HCC 特征高度相关。我们表明 ADAMTS12 在 HCC 患者的肿瘤基质细胞和相邻纤维组织中表达，更具体地说，在活化的星状细胞中表达。使用四氯化碳诱导的肝损伤小鼠模型，我们表明 Adamts12 在 24 小时急性处理后强烈且短暂表达，并且在接受四氯化碳诱导的慢性肝损伤的 Adamts12 缺失小鼠中纤维化加剧。使用 HSC 来源的 LX-2 细胞系，我们表明 ADAMTS12 的沉默导致基因表达谱发生深刻变化。特别是，先前报道在 HSC 激活时诱导的基因，如 PAI-1，在 ADAMTS12 敲低后大多下调。这些细胞的表型发生改变，向分化程度较低的状态转变，表现为肌动蛋白网络改变和核扩散减少。这些表型变化以及 PAI-1 的下调，通过 TGF-β 处理得到逆转。本研究因此将 ADAMTS12 鉴定为 HSC 分化的调节剂，也是慢性肝病的新参与者。
