Lösliches Endoglin (sCD105) : diagnostische Wertigkeit bei chronischen Lebererkrankungen und funktionelle Bedeutung für die Signaltransduction von transforming growth factor (TGF-beta)

Liver cirrhosis and chronic viral hepatitis-B and -C infections are well-known risk conditions for the development of HCC, and identification of HCC in high-risk patients, who are at a potentially curable stage, is still an unsolved clinical problem. Therefore, the diagnostic potential and value of solube endoglin in patients with liver cirrhosis at high-risk of HCC was investigated. In addition, we elucidated the functional impact of heterologously expressed soluble endoglin on TGF-b1/Smad3 signaling by using an artificial reporter system for the detection of phosphorylated Smad3, i.e. (CAGA)12-MLP Luc. For the evaluation of sCD105 as a marker for the occurence of HCC in high-risk patients, we measured the concentration of sCD105 in both, 121 patients of chronic liver disease visited Aachen university hospital during one year and 70 healthy individuals, constituting the control group. In parallel, AFP serum concentrations were measured, to compare the results of the sCD105 measurements with an established marker. The 121 patients were classified into 19 patients with liver fibrosis, 57 cirrhotic patients, 45 cirrhotic patients with HCC and 9 patients with HCC only. While sCD105 showed no significant difference in concentration between the healthy group with a median 3.7 µg/L and patients with first grade of liver fibrosis median 3.5 µg/L. The most important finding was the discriminatory potential of endoglin with respect to the severity of fibrosis first and malignant transformation as the second, i.e. that first sCD105 concentration showed a significant (P value = 0.0001) higher value in patients with cirrhosis having a median of 5.8 µg/L compared to the fibrotic group. On the other hand, there is a further significant increase in sCD105 concentration in the cirrhosis with HCC group (median 7.4 µg/L; P value = 0.0006) compared to the cirrhotic group. Moreover, sCD105 shows higher diagnostic sensitivity when compared to AFP (>= 90.9 vs. 81.8%) and there was only mild to moderate correlation between these two parameters in the latter groups. For the functional analysis, the rat soluble endoglin was first cloned, followed by the functional expression of the protein in TGF-b sensitive cells, i.e. L6E9 cells and primary hepatocytes. The presence of the soluble endoglin in both of these systems modulated the TGF-b1/Smad3 signaling as evaluated with the phospho-Smad3 specific reporter (CAGA)12-MLP Luc. From the reported data we conclude that circulating sCD105 may be a complementary marker to identify patients with liver cirrhosis who are at high-risk of HCC. However, further confirmatory studies are needed to evaluate the application potential of this novel serum marker in a large cohort of patients. In addition, we showed that soluble CD105 has a role in TGF-b signaling, as we could clearly show by the heterologous expression of the rat soluble endoglin. Therefore, it is most likely that the circulating soluble endoglin induces a pathophysiological effect by modulation of TGF-b signaling in responsive cells.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2007

Author dc:creator

• Rizk, Mohamed Soliman

Contributors dc:contributor

• Gressner, Axel M.

• info:eu-repo/classification/ddc/610
• Medizin
• Lösliches Endoglin
• Leberzirrhose
• HCC
• Soluble endoglin
• liver cirrhosis

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124053%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62487