<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway

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 <i>sulfatase</i>-2 (SULF2) in liver fibrosis. To this end, we induced li...

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Autores principales:	Ikuo Nakamura, Faizal Z. Asumda, Catherine D. Moser, Yoo Na N. Kang, Jin-Ping Lai, Lewis R. Roberts
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	liver fibrosis cirrhosis SULF2 transforming growth factor-β hepatocellular carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/cc40c55beceb4fb8940093a3f1e36b86
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spelling	oai:doaj.org-article:cc40c55beceb4fb8940093a3f1e36b862021-11-11T15:27:01Z<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway10.3390/cancers132152792072-6694https://doaj.org/article/cc40c55beceb4fb8940093a3f1e36b862021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5279https://doaj.org/toc/2072-6694Transforming 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 <i>sulfatase</i>-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (<i>Sulf2</i>-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl<sub>4</sub>) 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, CCl<sub>4</sub> and TAA injection in <i>Sulf2</i>-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the <i>Sulf2</i>-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.Ikuo NakamuraFaizal Z. AsumdaCatherine D. MoserYoo Na N. KangJin-Ping LaiLewis R. RobertsMDPI AGarticleliver fibrosiscirrhosisSULF2transforming growth factor-βhepatocellular carcinomaNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5279, p 5279 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	liver fibrosis cirrhosis SULF2 transforming growth factor-β hepatocellular carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	liver fibrosis cirrhosis SULF2 transforming growth factor-β hepatocellular carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ikuo Nakamura Faizal Z. Asumda Catherine D. Moser Yoo Na N. Kang Jin-Ping Lai Lewis R. Roberts <i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
description	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 <i>sulfatase</i>-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (<i>Sulf2</i>-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl<sub>4</sub>) 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, CCl<sub>4</sub> and TAA injection in <i>Sulf2</i>-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the <i>Sulf2</i>-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.
format	article
author	Ikuo Nakamura Faizal Z. Asumda Catherine D. Moser Yoo Na N. Kang Jin-Ping Lai Lewis R. Roberts
author_facet	Ikuo Nakamura Faizal Z. Asumda Catherine D. Moser Yoo Na N. Kang Jin-Ping Lai Lewis R. Roberts
author_sort	Ikuo Nakamura
title	<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
title_short	<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
title_full	<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
title_fullStr	<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
title_full_unstemmed	<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
title_sort	<i>sulfatase</i>-2 regulates liver fibrosis through the tgf-β signaling pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cc40c55beceb4fb8940093a3f1e36b86
work_keys_str_mv	AT ikuonakamura isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway AT faizalzasumda isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway AT catherinedmoser isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway AT yoonankang isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway AT jinpinglai isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway AT lewisrroberts isulfatasei2regulatesliverfibrosisthroughthetgfbsignalingpathway
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<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway

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