Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agrin is a multifunctional heparan sulfate proteoglycan originally discovered in the neuromuscular junctions and later observed in numerous other localizations. The presence of agrin in the liver, either healthy or diseased, has formerly not been reported. We detected agrin in minor amounts in the basement membranes of blood vessels and bile ducts in the healthy liver. The proliferation of bile ductules and the formation of new septal blood vessels in liver cirrhosis, as well as neoangiogenesis in the hepatocellular carcinoma (HCC) result in a dramatic increase in the quantity of agrin. Vascular and peribiliary basement membranes were strongly immunopositive for agrin in 29/29 human liver specimens with cirrhosis and HCC. However, sinusoidal walls of regenerative nodules in the cirrhotic liver consistently remained negative. Given the selectivity of agrin for tumor microvessels, agrin immunohistochemistry may prove helpful in recognizing malignant transformation in cirrhotic livers. Similar immunohistochemical observations were made on the liver of rats exposed to a combined cirrhosis/HCC induction treatment. In both human and rats, agrin probably originates from activated myofibroblasts, vascular smooth muscle cells and biliary epithelial cells. Increased agrin expression in human specimens, in the liver of 4/4 treated rats, as well as in isolated rat liver mesenchymal cells was verified by quantitative RT-PCR. Considering that agrin binds various growth factors, and it directly interacts with cell membrane receptors such as alphav-integrins, we hypothesize a stimulatory role for agrin in neoangiogenic processes such as tumor vascularization, and a supportive role in bile ductule proliferation.
 ...
PMID:Agrin, a novel basement membrane component in human and rat liver, accumulates in cirrhosis and hepatocellular carcinoma. 1698 29

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is the fifth most common malignancy worldwide. HCC typically develops in the cirrhotic liver. Our preliminary results indicated that agrin, a heparan sulfate proteoglycan (HSPG) detected by us for the first time in the liver, accumulates in the basement membranes (BMs) of the cirrhotic liver and HCC. This novel finding prompted us to investigate the role of agrin in the pathogenesis and differential diagnosis of HCC. First, the previously unspecified monoclonal antibody anti-HSPG clone 7E12 was verified as anti-agrin, using mass spectrometry. Our subsequent experiments were carried out on specimens from 131 patients with chronic liver disease and 18 individuals with healthy liver, from 4 rats subjected to cirrhosis/HCC induction and 1 untreated control rat, as well as from cultured cells. In both human and rats, significantly increased expression of agrin in cirrhosis and HCC was demonstrated by immunohistochemistry (IHC), Western blot, and quantitative RT-PCR. By double immunofluorescent studies, agrin was localized to the muscular layer of blood vessel walls, the BM of bile ducts and ductular reaction, the microvessel walls of HCC, and occasionally the BM of hepatocellular tumor cells. Colocalization, gene expression, and mRNA in situ hybridization experiments suggested that the sources of agrin include vascular smooth muscle cells, epithelial cells of bile ducts and ductules, activated mesenchymal cells in the stroma of hepatocellular tumors, and occasionally tumor hepatocytes. Agrin in the BMs of bile ducts and blood vessels is thought to play an important role in the survival of bile duct epithelium and vascular endothelium, respectively. Thus, agrin may contribute to the formation of ductular reaction and HCC neovessels. As opposed to HCC neovessels that were consistently found agrin-positive, normal and cirrhotic sinusoids were always devoid of agrin, raising the possibility that agrin IHC might be useful in the differential diagnosis of benign versus malignant hepatocellular lesions. Agrin IHC was performed on 68 benign lesions (8 large regenerative nodules, 23 low-grade and 7 high-grade dysplastic nodules, 30 liver adenomas) and 29 malignant lesions (8 small HCC, 21 HCC), and was evaluated semi-quantitatively. Based on the results of IHC for agrin as well as CD34, a decision algorithm was devised that differentiated benign and malignant parenchymal lesions with a sensitivity of 93.1% and a specificity of 92.6%. Hence, we propose that agrin IHC might help distinguish between malignant hepatocellular lesions and their benign mimickers.
 ...
PMID:[Selective deposition of agrin in the microvasculature of hepatocellular carcinoma: aspects in pathogenesis and differential diagnosis]. 1906 66

Evaluating the process and mechanism of fibrogenesis is essential in hepatocellular carcinoma (HCC), especially in hepatocyte transformation and oncogenic signaling. We evaluated the oncogenic role of agrin secreted by platelet-derived growth factor (PDGF)-induced hepatic stellate cell (HSC) in HCC. Cells were co-cultured to investigate the effect of activated HSC on hepatocytes. Liquid chromatography and protein profiling analysis were used to search the distinct proteins secreted in HSC supernatant. Sprague Dawley rats with Diethylnitrosamine (DEN)-induced HCC were used to simulate human liver cancer and sorafenib was administered to investigate its effect on hepatocarcinogenesis. A paired "two-tailed" Student t-test and chi-square tests was used for statistical analysis. PDGF acted as an activator of the HSC and sorafenib inhibits the activation by blocking the combination of PDGF and PDGF receptor. The supernatant of activated HSCs promoted the proliferation, metastasis, and invasion of HL-7702 and SMMC-7721, as well as epithelial-mesenchymal transition (EMT). Agrin found in the HSC supernatant showed the same effect on SMMC-7721 as to the supernatant of activated LX-2. Furthermore, downregulation of agrin by siRNA could decrease the proliferation, metastasis, and invasion of SMMC-7721, and promote MET. Sorafenib prevented DEN-induced hepatocarcinogenesis and could alleviate the liver inflammation and fibrosis. Sorafenib could improve the liver function of Sprague Dawley rats by decreasing the serum levels of ALT and AST. These results demonstrate thatPDGF is an effective activator of HSC and sorafenib could inhibit the activation. In vivo experiment suggested sorafenib could alleviate the hepatocarcinogenesis mediated through agrin secretion and could be potential candidate for treatment of cirrhosis.
 ...
PMID:Agrin para-secreted by PDGF-activated human hepatic stellate cells promotes hepatocarcinogenesis in vitro and in vivo. 2928 55