Sulfatase-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway

Cancers

Faizal Z. Asumda¹  Ikuo Nakamura²  Catherine D. Moser²  Jin-Ping Lai²  Lewis R. Roberts²  Yoo Na N. Kang² 

[1] Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA;Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA;

关键词: liver fibrosis;    cirrhosis;    SULF2;    transforming growth factor-β;    hepatocellular carcinoma;   

DOI  :  10.3390/cancers13215279

来源: DOAJ

【 摘 要 】

Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl₄) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson’s trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson’s trichrome and α-SMA staining after BDL, CCl₄ and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis.

【 授权许可】

Unknown