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Plasma protein biomarkers of hepatocellular carcinoma in HCV-infected alcoholic patients with cirrhosis.

Ferrín G, Rodríguez-Perálvarez M, Aguilar-Melero P, Ranchal I, Llamoza C, Linares CI, González-Rubio S, Muntané J, Briceño J, López-Cillero P, Montero-Álvarez JL, de la Mata M - PLoS ONE (2015)

Bottom Line: Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression.The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81).In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC.

View Article: PubMed Central - PubMed

Affiliation: Maimónides Institute for Biomedical Research in Córdoba (IMBIC), Reina Sofía University Hospital, Córdoba, Spain; Biomedical Research Centre Network, Digestive and Liver Diseases (CIBERehd), Córdoba, Spain.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world, with limited options for treatment unless timely diagnosed. Chronic hepatitis C virus (HCV) infection and persistent heavy alcohol consumption are independent risk factors for HCC development, which may induce a specific protein expression pattern different from those caused separately. The aim of the study was to identify protein biomarkers for the detection of HCC in HCV-infected alcoholic patients with cirrhosis in order to improve survival. We compared protein expression profiles of plasma samples from 52 HCV-infected alcoholic patients with and without HCC, using 2-D DIGE coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analyzed statistically using Decyder software, and verified by western-blot and ELISA. In plasma samples from HCV-infected alcoholic patients, we found significantly differential expression profiles of carboxypeptidase-N, ceruloplasmin (CP), complement component 4a (C4a), fibrinogen-alpha (FGA), immunoglobulin mu chain C region, serum albumin, and serum paraoxonase/arylesterase 1 (PON1). Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression. In the validation through ELISA, C4a serum concentration was increased in HCC patients (2.4±1 ng/mg vs 1.8±0.6 ng/mg; p = 0.029), being the only independent predictor of HCC in the multivariate analysis (OR = 2.15; p = 0.015), with an AUROC = 0.70. The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81). In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC. Among them, C4a, and its combination with CP, FGA and PON1, could be considered as potentially reliable biomarkers for the detection of HCC in HCV-infected alcoholic patients.

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Validation of selected candidate biomarkers for HCC development in a larger patient population.(A) Quantification of plasma concentration of CPN (pg/mg plasma protein), CP, IgM, PON1 (μg/mg plasma protein), C4a (ng/mg plasma protein) and FGA (μg/mg plasma protein) by ELISA. The sample size was 24 in the control group and 22 in the tumor group. * Statistically significant differences between groups. Data as mean ± standard error; (B) ROC curves showing that the best predictive ability to identify patients with HCC belongs to the combination of C4a, FGA, CP and PON1.
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pone.0118527.g003: Validation of selected candidate biomarkers for HCC development in a larger patient population.(A) Quantification of plasma concentration of CPN (pg/mg plasma protein), CP, IgM, PON1 (μg/mg plasma protein), C4a (ng/mg plasma protein) and FGA (μg/mg plasma protein) by ELISA. The sample size was 24 in the control group and 22 in the tumor group. * Statistically significant differences between groups. Data as mean ± standard error; (B) ROC curves showing that the best predictive ability to identify patients with HCC belongs to the combination of C4a, FGA, CP and PON1.

Mentions: To evaluate the utility of the identified proteins CPN, CP, C4a, FGA, IgM and PON1 as candidate biomarkers for HCC development in HCV-infected alcoholic patients, 46 plasma samples (24 from the control group and 22 from the tumor group) were subsequently analyzed by ELISA (Fig. 3A). The immunoassay confirmed the differential expression of C4a in HCC patients (2.4±1 ng/mg plasma protein) compared to patients without HCC (1.8±0.6 ng/mg) (p = 0.029). Average concentrations of FGA were increased in HCC patients (49.9±28 vs 25±12 μg/mg) (p<0.001). Although there were higher concentrations of CP in HCC patients (21.8 μg/mg [IQR 14–27]) than in controls (16.1 μg/mg [IQR 11–24]), these differences were marginally not significant (p = 0.071). Serum PON-1 concentration was 8.3 μg/mg [IQR 6–13] in HCC patients and 11.5 μg/mg [IQR 7–13] in controls (p = 0.31). The serum concentration of CPN was similar in HCC patients compared with controls without HCC (45.5±16.5 ng/mg vs. 44.9±20.1 ng/mg; p = 0.91), as it was IgM concentration (36.7±11 vs 40.5±15.5; p = 0.34).


Plasma protein biomarkers of hepatocellular carcinoma in HCV-infected alcoholic patients with cirrhosis.

Ferrín G, Rodríguez-Perálvarez M, Aguilar-Melero P, Ranchal I, Llamoza C, Linares CI, González-Rubio S, Muntané J, Briceño J, López-Cillero P, Montero-Álvarez JL, de la Mata M - PLoS ONE (2015)

Validation of selected candidate biomarkers for HCC development in a larger patient population.(A) Quantification of plasma concentration of CPN (pg/mg plasma protein), CP, IgM, PON1 (μg/mg plasma protein), C4a (ng/mg plasma protein) and FGA (μg/mg plasma protein) by ELISA. The sample size was 24 in the control group and 22 in the tumor group. * Statistically significant differences between groups. Data as mean ± standard error; (B) ROC curves showing that the best predictive ability to identify patients with HCC belongs to the combination of C4a, FGA, CP and PON1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4366144&req=5

pone.0118527.g003: Validation of selected candidate biomarkers for HCC development in a larger patient population.(A) Quantification of plasma concentration of CPN (pg/mg plasma protein), CP, IgM, PON1 (μg/mg plasma protein), C4a (ng/mg plasma protein) and FGA (μg/mg plasma protein) by ELISA. The sample size was 24 in the control group and 22 in the tumor group. * Statistically significant differences between groups. Data as mean ± standard error; (B) ROC curves showing that the best predictive ability to identify patients with HCC belongs to the combination of C4a, FGA, CP and PON1.
Mentions: To evaluate the utility of the identified proteins CPN, CP, C4a, FGA, IgM and PON1 as candidate biomarkers for HCC development in HCV-infected alcoholic patients, 46 plasma samples (24 from the control group and 22 from the tumor group) were subsequently analyzed by ELISA (Fig. 3A). The immunoassay confirmed the differential expression of C4a in HCC patients (2.4±1 ng/mg plasma protein) compared to patients without HCC (1.8±0.6 ng/mg) (p = 0.029). Average concentrations of FGA were increased in HCC patients (49.9±28 vs 25±12 μg/mg) (p<0.001). Although there were higher concentrations of CP in HCC patients (21.8 μg/mg [IQR 14–27]) than in controls (16.1 μg/mg [IQR 11–24]), these differences were marginally not significant (p = 0.071). Serum PON-1 concentration was 8.3 μg/mg [IQR 6–13] in HCC patients and 11.5 μg/mg [IQR 7–13] in controls (p = 0.31). The serum concentration of CPN was similar in HCC patients compared with controls without HCC (45.5±16.5 ng/mg vs. 44.9±20.1 ng/mg; p = 0.91), as it was IgM concentration (36.7±11 vs 40.5±15.5; p = 0.34).

Bottom Line: Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression.The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81).In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC.

View Article: PubMed Central - PubMed

Affiliation: Maimónides Institute for Biomedical Research in Córdoba (IMBIC), Reina Sofía University Hospital, Córdoba, Spain; Biomedical Research Centre Network, Digestive and Liver Diseases (CIBERehd), Córdoba, Spain.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world, with limited options for treatment unless timely diagnosed. Chronic hepatitis C virus (HCV) infection and persistent heavy alcohol consumption are independent risk factors for HCC development, which may induce a specific protein expression pattern different from those caused separately. The aim of the study was to identify protein biomarkers for the detection of HCC in HCV-infected alcoholic patients with cirrhosis in order to improve survival. We compared protein expression profiles of plasma samples from 52 HCV-infected alcoholic patients with and without HCC, using 2-D DIGE coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analyzed statistically using Decyder software, and verified by western-blot and ELISA. In plasma samples from HCV-infected alcoholic patients, we found significantly differential expression profiles of carboxypeptidase-N, ceruloplasmin (CP), complement component 4a (C4a), fibrinogen-alpha (FGA), immunoglobulin mu chain C region, serum albumin, and serum paraoxonase/arylesterase 1 (PON1). Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression. In the validation through ELISA, C4a serum concentration was increased in HCC patients (2.4±1 ng/mg vs 1.8±0.6 ng/mg; p = 0.029), being the only independent predictor of HCC in the multivariate analysis (OR = 2.15; p = 0.015), with an AUROC = 0.70. The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81). In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC. Among them, C4a, and its combination with CP, FGA and PON1, could be considered as potentially reliable biomarkers for the detection of HCC in HCV-infected alcoholic patients.

Show MeSH
Related in: MedlinePlus