SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis

被引：51

作者：

Athwal, Varinder S. ^{[1
,2
]}

Pritchett, James ^{[3
]}

Llewellyn, Jessica ^{[1
]}

Martin, Katherine ^{[1
,2
]}

Camacho, Elizabeth ^{[4
]}

Raza, Sayyid M. A. ^{[1
,2
]}

Phythian-Adams, Alexander ^{[5
]}

Birchall, Lindsay J. ^{[1
,2
]}

Mullan, Aoibheann F. ^{[1
,2
]}

Su, Kim ^{[1
,2
]}

Pearmain, Laurence ^{[1
,2
]}

Dolman, Grace ^{[6
,7
,8
]}

Zaitoun, Abed M. ^{[9
,10
,11
]}

Friedman, Scott L. ^{[12
]}

MacDonald, Andrew ^{[5
]}

Irving, William L. ^{[6
,7
,8
,10
,11
,13
]}

Guha, Indra N. ^{[6
,7
,8
]}

Hanley, Neil A. ^{[1
,2
]}

Hanley, Karen Piper ^{[1
,2
]}

机构：

[1] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Div Diabet Endocrinol & Gastroenterol, Manchester, Lancs, England

[2] Cent Manchester Univ Hosp NHS Fdn Trust, Res & Innovat Div, Manchester, Lancs, England

[3] Manchester Metropolitan Univ, Sch Healthcare Sci, Manchester, Lancs, England

[4] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Ctr Hlth Econ,Inst Populat Hlth, Manchester, Lancs, England

[5] Univ Manchester, Fac Life Sci, Manchester Ctr Collaborat Inflammat Res, Manchester, Lancs, England

[6] Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Ctr, Nottingham Digest Dis Ctr, Nottingham, England

[7] Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Ctr, NIHR, Nottingham, England

[8] Univ Nottingham, Nottingham, England

[9] Univ Nottingham, Nottingham Digest Dis Ctr, Dept Cellular Pathol, Nottingham, England

[10] Univ Nottingham, Natl Inst Hlth Res Biomed Res Unit Gastroenterol, Nottingham, England

[11] Nottingham Univ Hosp NHS Trust, Nottingham, England

[12] Icahn Sch Med Mt Sinai, Div Liver Dis, New York, NY 10029 USA

[13] Univ Nottingham, Sch Life Sci, Nottingham Digest Dis Ctr, Nottingham, England

来源：

EMBO MOLECULAR MEDICINE | 2017年 / 9卷 / 12期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

extracellular matrix; hepatic stellate cells; liver fibrosis; SOX9; YAP1; HEPATIC STELLATE CELLS; TO-MESENCHYMAL TRANSITION; AUTOSOMAL SEX REVERSAL; C VIRUS-INFECTION; SRY-RELATED GENE; CAMPOMELIC DYSPLASIA; TRANSCRIPTION FACTORS; HUMAN PANCREAS; RISK SCORE; BILE-DUCTS;

D O I：

10.15252/emmm.201707860

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation invivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.

引用

页码：1696 / 1710

页数：15

共 58 条

[1]

Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa [J].