Complement Factor H as a Marker for Detection of Bladder Cancer

Cheng, Zhu-Zhu; Corey, Michael J.; Pärepalo, Maria; Majno, Sandra; Hellwage, Jens; Zipfel, Peter F.; Kinders, Robert J.; Raitanen, Mika; Meri, Seppo; Jokiranta, T. Sakari

doi:10.1373/clinchem.2004.042192

Cited by 59 publications

(39 citation statements)

References 30 publications

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“…This central fluid phase protein regulates the alternative pathway of the complement system (17)(18)(19). cfH was expressed in various malignant cell lines including ovarian, colon, bladder, liver and lung cancer cell lines (6,10,(20)(21)(22). it binds to c3b and blocks the alternative pathway of complement by i) acting as cofactor for c3b cleavage, ii) accelerating the decay of the alternative c3 convertase, and iii) preventing binding of factor B to c3.…”

Section: Discussionmentioning

confidence: 99%

Human complement factor H is a novel diagnostic marker for lung adenocarcinoma

Petersen¹

2011

Int J Oncol

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Abstract.Human complement factor H (cfH), a central complement control protein, is a member of the regulators of complement activation family. recent studies suggested that cfH may play a key role in the resistance of complementmediated lysis in various cancer cells. in this study, we investigated the role of cfH in human lung cancer. expression of cfH was analyzed in lung cancer cell lines by rt-Pcr, Western blotting and immunofluorescence. In primary lung tumors, the protein expression of cfH was evaluated by immunohistochemistry (iHc) on tissue microarray (tMa). Binding of cfH to lung cancer cells was detected by flow cytometry. mrna expression of cfH was detected in 6 out of 10 non-small cell lung cancer (nSclc) cell lines, but in none of the small cell lung cancer (Sclc) cell lines. in line with Western blotting, immunofluorescence analysis demonstrated cfH protein expression in 3 nSclc cell lines, and the immunoreaction was mainly associated with cell cytoplasm and membrane. in primary lung tumors, 54 out of 101 samples exhibited high expression of cfH and high expression was significantly correlated with lung adenocarcinoma (p=0.009). also, in adenocarcinoma of the lung, Kaplan-Meier survival analysis showed a tendency that cfH-positive tumors had worse prognosis in comparison to cfH-negative tumors (p=0.082). Additionally, shorter survival time of patients with adenocarcinoma (<20 months) was associated with higher staining of CFH (p=0.033). Our data showed that non-small cell lung cancer cells expressed and secreted cfH. cfH might be a novel diagnostic marker for human lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Human complement factor H is a novel diagnostic marker for lung adenocarcinoma

Petersen¹

2011

Int J Oncol

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“…The detection of CFH with a polyclonal anti-CFH antibody on Western blot resulted in the visualization of two intense bands (50 and 170 kDa) among other weaker ones (data not shown). According to the molecular weight, the higher band most likely corresponded to the complete form of CFH, whereas the lower one might correspond to the factor H-like protein 1 (FHL-1), obtained from alternative splicing (29). However, when considered together or separately, the volumes of the two bands were not significantly different between the S1 and S2 groups (Table III and Fig.…”

Section: Ments 8 With the Ltq-ot Only And 22 With The Maldi Tof-tofmentioning

confidence: 93%

Discovery and Verification of Osteopontin and Beta-2-microglobulin as Promising Markers for Staging Human African Trypanosomiasis

Tiberti¹,

Hainard²,

Lejon

et al. 2010

Molecular & Cellular Proteomics

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Human African trypanosomiasis, or sleeping sickness, is a parasitic disease endemic in sub-Saharan Africa, transmitted to humans through the bite of a tsetse fly. The first or hemolymphatic stage of the disease is associated with presence of parasites in the bloodstream, lymphatic system, and body tissues. If patients are left untreated, parasites cross the blood-brain barrier and invade the cerebrospinal fluid and the brain parenchyma, giving rise to the second or meningoencephalitic stage. Stage determination is a crucial step in guiding the choice of treatment, as drugs used for S2 are potentially dangerous. Current staging methods, based on counting white blood cells and demonstrating trypanosomes in cerebrospinal fluid, lack specificity and/or sensitivity. In the present study, we used several proteomic strategies to discover new markers with potential for staging human African trypanosomiasis. Cerebrospinal fluid (CSF) samples were collected from patients infected with Trypanosoma brucei gambiense in the Democratic Republic of Congo. The stage was determined following the guidelines of the national control program. The proteome of the samples was analyzed by two-dimensional gel electrophoresis (n ‫؍‬ 9), and by sixplex tandem mass tag (TMT) isobaric labeling (n ‫؍‬ 6) quantitative mass spectrometry. Overall, 73 proteins were overexpressed in patients presenting the second stage of the disease. Two of these, osteopontin and ␤-2-microglobulin, were confirmed to be potential markers for staging human African trypanosomiasis (HAT) by Western blot and ELISA. The two proteins significantly discriminated between S1 and S2 patients with high sensitivity (68% and 78%, respectively) for 100% specificity, and a combination of both improved the sensitivity to 91%. The levels of osteopontin and ␤-2-microglobulin in CSF of S2 patients (g/ml range), as well as the fold increased concentration in S2 compared with S1 (3.8 and 5.5 respectively) make the two markers good candidates for the development of a test for staging HAT patients. Molecular & Cellular Proteomics 9:2783-2795, 2010.

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“…Mutagenesis, expression, and purification have been previously described for FH19-20 (27), most FH19-20 mutants (13), and C3d (or C3dg) and C3dg mutants (28). FH constructs were expressed in Pichia pastoris and C3d or C3dg constructs in Escherichia coli.…”

Section: Methodsmentioning

confidence: 99%

Dual interaction of factor H with C3d and glycosaminoglycans in host–nonhost discrimination by complement

Kajander

Lehtinen

Hyvärinen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The alternative pathway of complement is important in innate immunity, attacking not only microbes but all unprotected biological surfaces through powerful amplification. It is unresolved how host and nonhost surfaces are distinguished at the molecular level, but key components are domains 19-20 of the complement regulator factor H (FH), which interact with host (i.e., nonactivator surface glycosaminoglycans or sialic acids) and the C3d part of C3b. Our structure of the FH19-20:C3d complex at 2.3-Å resolution shows that FH19-20 has two distinct binding sites, FH19 and FH20, for C3b. We show simultaneous binding of FH19 to C3b and FH20 to nonactivator surface glycosaminoglycans, and we show that both of these interactions are necessary for full binding of FH to C3b on nonactivator surfaces (i.e., for target discrimination). We also show that C3d could replace glycosaminoglycan binding to FH20, thus providing a feedback control for preventing excess C3b deposition and complement amplification. This explains the molecular basis of atypical hemolytic uremic syndrome, where mutations on the binding interfaces between FH19-20 and C3d or between FH20 and glycosaminoglycans lead to complement attack against host surfaces. structure and function | X-ray crystallography | hemolysis | kidney diseases | human mutations P reviously unencountered microbes invading a human body must be rapidly recognized and eliminated. This is the function of innate immunity, which includes the alternative pathway (AP) of complement. AP components can attack targets with hydroxyl or amine groups (i.e., all biological surfaces). This is a powerful defense mechanism, because there is rapid amplification leading to efficient opsonization or target lysis by the membrane attack complex (MAC). The AP attack is, therefore, also potentially dangerous for the host if one's cells and acellular structures are not protected.The AP activation is based on spontaneous hydrolysis of C3 in plasma leading to production of C3b, which then randomly attaches onto any surface hydroxyl or amine group through a reactive thioester located on the C3d part [i.e., thioester domain (TED)] of C3b. If these surface-attached C3b molecules are not quickly inactivated to iC3b and C3d, C3b deposition is rapidly amplified by a positive enzymatic feedback loop, leading to opsonophagocytosis and formation of the lytic membrane attack complex. On host surfaces, which are naturally nonactivators of the AP, efficient down-regulation of bound C3b occurs in three ways: factor I-mediated cleavage of C3b to inactive iC3b, acceleration of the decay of the preformed C3 convertases, or inhibition of factor B binding to C3b. Factor H (FH) is required for all these. It also down-regulates C3b deposition on noncellular surfaces, such as the heparan sulfate-rich glomerular basement membrane. FH is, thus, essential for restricting AP attack against host surfaces while allowing AP attack against foreign surfaces (i.e., for target discrimination) (1). A long-standing central question in complemen...

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Complement Factor H as a Marker for Detection of Bladder Cancer

Cited by 59 publications

References 30 publications

Human complement factor H is a novel diagnostic marker for lung adenocarcinoma

Human complement factor H is a novel diagnostic marker for lung adenocarcinoma

Discovery and Verification of Osteopontin and Beta-2-microglobulin as Promising Markers for Staging Human African Trypanosomiasis

Dual interaction of factor H with C3d and glycosaminoglycans in host–nonhost discrimination by complement

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