TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

被引：56

作者：

Dropmann, Anne ^{[1
]}

Dediulia, Tatjana ^{[1
]}

Breitkopf-Heinlein, Katja ^{[2
]}

Korhonen, Hanna ^{[3
]}

Janicot, Michel ^{[3
]}

Weber, Susanne N. ^{[4
]}

Thomas, Maria ^{[5
,6
]}

Piiper, Albrecht ^{[7
]}

Bertran, Esther ^{[8
,9
]}

Fabregat, Isabel ^{[8
,9
]}

Abshagen, Kerstin ^{[10
]}

Hess, Jochen ^{[11
,12
]}

Angel, Peter ^{[13
]}

Coulouarn, Cedric ^{[14
]}

Dooley, Steven ^{[1
]}

Meindl-Beinker, Nadja M. ^{[1
]}

机构：

[1] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Mol Hepatol, Heidelberg, Germany

[2] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Heidelberg, Germany

[3] Isarna Therapeut GmbH, Munich, Germany

[4] Univ Saarland, Med Ctr, Dept Med 2, Homburg, Germany

[5] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany

[6] Univ Tubingen, Tubingen, Germany

[7] Univ Frankfurt Klinikum, Med Klin 1, Frankfurt, Germany

[8] Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain

[9] Univ Barcelona LHospitalet, Barcelona, Spain

[10] Univ Rostock, Med Ctr, Inst Expt Surg, D-18055 Rostock, Germany

[11] German Canc Res Ctr, Res Grp Mol Mech Head & Neck Tumors, Heidelberg, Germany

[12] Univ Heidelberg Hosp, Dept Otolaryngol Head & Neck Surg, Sect Expt & Translat Head & Neck Oncol, Heidelberg, Germany

[13] German Canc Res Ctr, DKFZ ZMBH Alliance, Div Signal Transduct & Growth Control, Heidelberg, Germany

[14] Univ Rennes, Pontchaillou Univ Hosp, INSERM, UMR991, Rennes, France

来源：

ONCOTARGET | 2016年 / 7卷 / 15期

关键词：

TGF-beta isoform; mouse models; HCC; fibrosis; regeneration; GROWTH-FACTOR-BETA; HUMAN HEPATOCELLULAR-CARCINOMA; HEPATIC STELLATE CELLS; TGF-BETA; GENE-EXPRESSION; TRANSFORMING GROWTH-FACTOR-BETA-1; IN-VITRO; HUMAN CANCER; HEPATOCYTE PROLIFERATION; SIGNALING RECEPTORS;

D O I：

10.18632/oncotarget.6967

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

TGF-beta 1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-beta 2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-beta 2 expression correlates with fibrogenesis and liver cancer development. Using quantitative realtime PCR and ELISA, we show that TGF-beta 2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-beta 2 stimulation of the LX-2 cells led to upregulation of the TGF-beta receptors 1, 2, and 3, whereas TGF-beta 1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-beta 2 expression was accompanied by TGF-beta 1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-beta 2 upregulation correlated with fibrotic markers and was more prominent than TGF-beta 1 expression. Accordingly, MDR2-KO mice showed significant TGF-beta 2 upregulation within 3 to 15 months but minor TGF-beta 1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-beta 2 expression and secretion were observed, with some cell lines even secreting more TGF-beta 2 than TGF-beta 1. TGF-beta 2 was also upregulated in tumors of TGF alpha/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-beta 2 as compared to normal liver. Our study demonstrates upregulation of TGF-beta 2 in liver disease and suggests TGF-beta 2 as a promising therapeutic target for tackling fibrosis and HCC.

引用

页码：19499 / 19518

页数：20

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