Abstract
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated during hepatic fibrogenesis and considered to promote fibrosis in the injured liver by inhibition of matrix metalloproteases (MMP) and degradation of extracellular matrix. Moreover, TIMP-1 displays anti-apoptotic properties, in patients with hepatocellular carcinoma (HCC) TIMP-1 serum levels are elevated and high TIMP-1 expression levels in HCC are associated with a poor prognosis. Therefore, TIMP-1 could functionally link fibrogenesis and carcinogenesis in the liver. The aim of our study was to characterize the role of TIMP-1 in hepatic fibrogenesis and carcinogenesis. Experimental hepatic fibrogenesis as well as diethylnitrosamine (DEN) -induced hepatocarcinogenesis were studied in TIMP-1-deficient mice and wild type littermates. Hepatic TIMP-1 expression was upregulated following induction of liver fibrosis by bile duct ligation (BDL) or by carbon tetrachloride (CCl4). Unexpectedly, in comparison to wild type littermates, TIMP-1-deficient mice were not protected from liver fibrosis induced by BDL or CCl4. TIMP-1 expression was significantly higher in HCC nodules than in surrounding liver tissue. However, experimental hepatic carcinogenesis was similar in TIMP-1-deficient mice and wild type littermates following DEN-treatment or combined treatment with DEN and CCl4. Therefore we concluded that TIMP-1 is not essential for hepatic fibrogenesis and carcinogenesis in mice.
Highlights
Chronic liver injury, irrespective of the underlying disease, triggers a wound healing response that leads to fibrogenesis and can result in the development of liver cirrhosis
Profibrogenic and carcinogenic functions have been attributed to Tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-1 expression levels have been shown to correlate with liver fibrosis and presence of hepatocellular carcinoma[5,6,7,8, 25]
We study the functional relevance of TIMP-1 in the development of liver fibrosis and hepatocellular carcinoma in vivo
Summary
Irrespective of the underlying disease, triggers a wound healing response that leads to fibrogenesis and can result in the development of liver cirrhosis. Underlying liver cirrhosis represents a major predisposition for the development of hepatocellular carcinoma (HCC)[1, 2]. In spite of the unique epidemiologic association between liver cirrhosis and HCC it is still unclear how the cirrhotic microenvironment contributes to hepatic carcinogenesis. Several functional studies in mice with either transgenic TIMP-1 overexpression or using an antibody or MMP-9 mutants to antagonize TIMP-1 in vivo suggest that TIMP-1 promotes hepatic fibrogenesis[10,11,12,13]. High TIMP-1 serum levels are significantly correlated with the presence of HCC in patients with chronic liver disease[25]. TIMP-1 harbors functions that might contribute to both, hepatic fibrogenesis and carcinogenesis, and has been epidemiologically associated with liver fibrosis and HCC. We investigate the role of TIMP-1 as a potential link between hepatic fibrogenesis and carcinogenesis in wild type and TIMP-1-deficient mice
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