Human Mac-2 Binding Protein Research Articles

Lysyl oxidase-like 2 as a predictor of hepatocellular carcinoma in patients with hepatitis C virus after sustained virological response

Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p < 0.001). Post-Tx LOXL2 levels, fibrosis-4 index, platelet counts, Wisteria floribunda agglutinin-positive human Mac-2 binding protein levels, and alpha-fetoprotein (AFP) levels were identified as independent predictive factors for post-SVR HCC development in the univariate analysis. The incidence of post-SVR HCC development was significantly higher in patients with post-Tx LOXL2 levels ≥ 2.08 ng/mL and AFP levels ≥ 5.0 ng/mL than in patients with elevated levels of either marker or with lower marker levels. Serum LOXL2 levels can serve as a predictive biomarker for HCC development after achieving SVR. The combination of serum LOXL2 and AFP levels provides robust risk stratification for HCC development after SVR, suggesting an enhanced surveillance strategy.

Serum wisteria floribunda agglutinin-positive human Mac-2 binding protein is unsuitable as a diagnostic marker of occult hepatocellular carcinoma in end-stage liver cirrhosis.

Serum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) is a marker of liver fibrosis and hepatocellular carcinoma (HCC). In this study, we aimed to evaluate the diagnostic ability of WFA+-M2BP for occult HCC, which current diagnostic imaging tests fail to detect. Patients who underwent hepatectomy for liver transplantation (LT) and whose whole liver could be sliced and subjected to histological examination between 2010 and 2018 were eligible for this study (n = 89). WFA+-M2BP levels were measured in samples collected before the LT. Comparison of the postoperative histological test results with the preoperative imaging data grouped the patients into histologically no group (N), histologically detected group (D), histologically increased group (I), and histologically decreased or same group (DS), and the results were compared with the WFA+-M2BP values. In addition, comparisons were made between each data with and without HCC, including occult HCC, and total tumor diameter. Irrespective of underlying hepatic disease conditions, there were 6 patients in the N group, 10 in the D group, 41 in the I group, and 32 in the DS group. The median of the serum WFA+-M2BP level for each group was as follows: N group, 8.05 (1.25-11.9); D group, 11.025 (1.01-18.21); I group, 9.67 (0.29-17.83); and DS group, 9.56 (0.28-19.44) confidence of interval. We found no significant differences between the pairings. Comparison of underlying hepatic diseases revealed that liver cirrhosis due to hepatitis B and C and non-B and -C liver cirrhosis had no significant differences. AFP levels, on the other hand, had significant relationships in comparison between the presence or absence of histological HCC, in correlation between total tumor diameter, and in the ROC analysis for the diagnosis of HCC including occult HCC. Serum WFA+-M2BP cannot help diagnose occult HCC that is already undetected using imaging tests in decompensated liver cirrhosis patients requiring LT.

Use of the Serum Wisteria floribunda Agglutinin-Positive Mac2 Binding Protein as a Marker of Gastroesophageal Varices and Liver-Related Events in Chronic Hepatitis C Patients.

Background: A test to narrow down patients who require esophagogastroduodenoscopy (EGD) with a high probability of having gastroesophageal varices (GEV) and a high-risk of liver-related events is an unmet need. Methods: The measurement of serum fibrosis markers and EGD was performed in 166 consecutive chronic hepatitis C patients. The correlation between the grades of GEV and fibrosis markers and the subsequent occurrence of liver-related and fibrosis markers were examined. Results: Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+–M2BP) levels increased according to the grade of GEV (3.4 (0.2–18.6) for no GEV, 7.9 (1.8–20.0) for small GEV, and 11.4 (4.0–20.0) for large GEV; p < 0.001). The diagnostic accuracy of the WFA+–M2BP was superior compared to other serum fibrosis markers, and WFA+–M2BP was an independent predictor of GEV in the multivariate analysis. Furthermore, the cumulative incidence of liver-related events at one year was 2.3% in patients with WFA+–M2BP levels ≤ 7.0 and 37.5% in patients with WFA+–M2BP levels > 7.0 (p < 0.001). WFA+–M2BP > 7.0 was a significant predictive factor for liver-related events (Hazard ratio 6.7, p = 0.004) independent of Child–Pughclass. Conclusions: WFA+–M2BP could be used to estimate the presence and grade of GEV and is linked to liver-related events in chronic hepatitis C patients.

Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection.

Background/AimsTo investigate whether serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) can predict the recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection.MethodsPatients with chronic hepatitis B (CHB) who underwent curative resection for HCC between 2004 and 2015 were eligible for the study. Recurrence was sub-classified as early (<2 years) or late (≥2 years).ResultsA total of 170 patients with CHB were selected. During the follow-up period (median, 22.6 months), 64 (37.6%) patients developed recurrence. In multivariate analyses, WFA+-M2BP level was an independent predictor of overall (hazard ratio [HR]=1.490), early (HR=1.667), and late recurrence (HR=1.416), together with male sex, des-gamma carboxyprothrombin level, maximal tumor size, portal vein invasion, and satellite nodules (all P<0.05). However, WFA+-M2BP level was not predictive of grade B-C posthepatectomy liver failure. The cutoff value that maximized the sum of sensitivity (30.2%) and specificity (90.6%) was 2.14 (area under receiver operating characteristic curve=0.632, P=0.010). Patients with a WFA+-M2BP level >2.14 experienced recurrence more frequently than those with a WFA+-M2BP level ≤2.14 (P=0.011 by log-rank test), and had poorer postoperative outcomes than those with a WFA+-M2BP level ≤2.14 in terms of overall recurrence (56.0 vs. 34.5%, P=0.047) and early recurrence (52.0 vs. 20.7%, P=0.001).ConclusionsWFA+-M2BP level is an independent predictive factor of HBV-related HCC recurrence after curative resection. Further studies should investigate incorporation of WFA+-M2BP level into tailored postoperative surveillance strategies for patients with CHB.

Peritransplant kinetics of Mac-2-binding protein glycosylation isomer levels in living donor liver transplantation: its implication of posttransplant small-for-size syndrome.

Wisteria floribunda agglutinin positive human Mac-2 binding protein glycosylation isomer (M2BPGi) has recently developed as a noninvasive serum marker of liver fibrosis. Liver transplant candidates usually have high serum levels of M2BPGi due to advanced cirrhosis. The aim of the present study was to elucidate the kinetics of serum M2BPGi after liver transplantation and the relationships between the level of M2BPGi and graft function. Fifteen recipients who underwent living donor liver transplantation (LDLT) between June 2015 and January 2016 and whose pretransplant, postoperative day (POD) 1, POD 3, and POD 7 sera were available for measuring M2BPGi were enrolled in this study. Small-for-size syndrome (SFSS) was defined as the presence of cholestasis (total bilirubin >10 mg/dL) on POD 7 and intractable ascites (>1 L/day on POD 14 or >500 ml/day on POD 28) without other specific causes. The median of pretransplant M2BPGi was 9.75 cutoff index (C.O.I.) (range, 3.04-24.49). There was neither any correlation between pretransplant M2BPGi and Model for End-Stage Liver Disease scores (r=0.416, P=0.123) nor Child-Turcotte-Pugh scores (r=-0.221, P=0.428). The levels of M2BPGi dramatically decreased after LDLT (median; 1.48 on POD 1, 1.47 on POD 3, 1.49 on POD 7). However, serum levels of M2BPGi rose again on POD 7 in some recipients and all 4 recipients with serum levels of M2BPGi exceeding 3.00 C.O.I. succumbed to SFSS later. When the cutoff of M2BPGi on POD 7 for predicting SFSS was determined to be 3.06 according to its receiver operating characteristic curve, both the sensitivity and the specificity for predicting later SFSS were 100%. The levels of M2BPGi dramatically decreased after LDLT. A re-rise of M2BPGi predicted later development of SFSS.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein in decompensated cirrhosis.

An assay for Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) has been reported as a useful non-invasive marker for the evaluation of the staging of fibrosis in several chronic liver diseases. However, available data on the effect of WFA+ -M2BP level in decompensated cirrhosis patients were limited. It is important that these investigations can validate the diagnostic utility of WFA+ -M2BP in the full range of patients with liver cirrhosis. A multicenter study was conducted at five locations in Japan. A total of 207 patients with liver cirrhosis were enrolled in the present study. To determine whether or not the WFA+ -M2BP value was associated with a progression of fibrosis among cirrhosis, this study examined WFA+ -M2BP levels between patients with cirrhosis in the decompensated and compensated groups. The numbers and proportions of compensated and decompensated patients were 113 (54.6%) and 94 (45.4%), respectively. The average WFA+ -M2BP levels were 2.22±1.61 in the compensated group and 6.91±5.04 in the decompensated group. Significantly higher WFA+ -M2BP levels were observed in the decompensated group than those in the compensated group (P<0.0001). The respective cut-off index values for decompensated cirrhosis were estimated using receiver-operating characteristic curves for WFA+ -M2BP levels. Using a cut-off index value of 3.37 for WFA+ -M2BP, predicting decompensated cirrhosis had a sensitivity of 77.8% and a specificity of 86.7%. WFA+ -M2BP values were higher in patients with decompensated liver cirrhosis.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts liver cancer development in chronic hepatitis B patients under antiviral treatment.

AIMThe risk factors for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients with undetectable serum HBV DNA under nucleos(t)ide analogue (NA) therapy are not well defined. We aimed to examine the relationship between Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) and HCC development in these patients.ResultsThere was a significant difference in the median levels of pre-treatment WFA+-M2BP between the HCC and control groups (0.67 vs 0.41 COI, respectively, p < 0.001). Among patients with cirrhosis, the median level of WFA+-M2BP was higher in HCC group than in control group (0.74 vs 0.47 COI, respectively, p = 0.014). Among patients without cirrhosis, the median level of WFA+-M2BP of HCC group was also higher (0.48 vs 0.28 COI, respectively, p = 0.002). With a cutoff value of 0.69, the AUROC of pre-treatment WFA+-M2BP to predict HCC development for the whole cohort was 0.70. With cutoff values of 0.69 and 0.34, the AUROCs to predict HCC were 0.67 and 0.77 for patients with and without cirrhosis, respectively.Materials and MethodsFifty-seven NA-treated patients with undetectable HBV DNA who developed HCC were compared with 57 controls (matched with demographics and treatment duration). WFA+-M2BP levels were measured, and expressed as cutoff index (COI). Subgroup analyses were also performed in patients with and without cirrhosis.ConclusionsA higher pre-treatment WFA+-M2BP level was associated with an increased risk of HCC development in patients with undetectable HBV DNA under NA therapy. Further longitudinal studies are required to examine the role of WFA+-M2BP as an accessory risk marker for HCC development.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts the risk of HBV-related liver cancer development.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) can be used to assess the degree of liver fibrosis, but few studies have investigated its prognostic utility. We evaluated whether serum WFA+ -M2BP can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. A total of 1323 CHB patients with WFA+ -M2BP test results between 2009 and 2011 were included in this retrospective analysis. The mean age of patients (793 men) was 51.0years. During the follow-up period (median 60.3months), 52 (3.9%) patients developed HCC. Age, the proportion of male gender, the presence of diabetes and cirrhosis, and levels of aspartate aminotransferase, alpha-foetoprotein, and WFA+ -M2BP were significantly greater in patients with HCC than in those without HCC, whereas serum albumin levels and platelet counts were significantly lower in patients with HCC than in those without HCC (all P<.05). In multivariate analysis, WFA+ -M2BP level was an independent predictor of HCC development (adjusted hazard ratio 1.143, 95% CI: 1.139-1.829), along with male gender and diabetes (all P<.05). In patients without cirrhosis (n=1087), WFA+ -M2BP levels ≥1.8 were associated with a higher risk of HCC development (P<.001 by log-rank test), whereas WFA+ -M2BP levels ≥1.8 tended to be associated with a higher risk of HCC development in patients with cirrhosis (n=236) (P=.073 by log-rank test). WFA+ -M2BP level can independently predict HCC development. Further studies should investigate whether WFA+ -M2BP level could be incorporated into surveillance strategies for CHB patients.

Use of Wisteria Floribunda Agglutinin-Positive Human Mac-2 Binding Protein in Assessing Risk of Hepatocellular Carcinoma Due to Hepatitis B Virus.

Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) is a serologic marker corresponding with degree of hepatic fibrosis. We evaluated its accuracy in assessing hepatic fibrosis and in predicting the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).In a 5-year period (2009–2013), a total of 95 CHB patients with available serum WFA+-M2BP assay and transient elastography assessment [to assess liver stiffness (LS)] who had undergone liver biopsy were recruited for retrospective analysis.Areas under the receiver operating characteristic curve for predicting fibrosis stages via serum WFA+-M2BP level were as follows: ≥F2, 0.688; ≥F3, 0.694; and F4, 0.704 (all P < 0.05). During the follow-up period (median, 45 months), HCC developed in 7 patients (7.4%). In patients with HCC, age, use of antiviral therapy, test parameters (HBV DNA, WFA+-M2BP, and LS determinations), and histologic stage of fibrosis were all significantly greater than in those free of HCC, whereas platelet count was significantly lower (all P < 0.05). On multivariate analysis, WFA+-M2BP was found independently predictive of emergent HCC [hazard ratio (HR) = 2.375; P = 0.036], although LS and histologic stage of fibrosis were not (P > 0.05). Risk of developing HCC was significantly greater in patients with high WFA+-M2BP levels (≥1.8) (adjusted HR = 11.5; P = 0.025). Cumulative incidence rates of HCC were also significantly higher in patients with high (vs. low) levels of WFA+-M2BP (log-rank test, P = 0.016).WFA+-M2BP determination significantly reflected degree/extent of hepatic fibrosis and independently predicted the risk of developing HCC in patients with CHB.

Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Values Predict the Development of Hepatocellular Carcinoma among Patients with Chronic Hepatitis C after Sustained Virological Response.

Measurement of Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) in serum was recently shown to be a noninvasive method to assess liver fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP values to predict the development of hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) by interferon treatment. For this purpose, we retrospectively analyzed 238 patients with SVR who were treated with interferon in our department. Serum WFA+-M2BP values were measured at pre-treatment (pre-Tx), post-treatment (24 weeks after completion of interferon; post-Tx), the time of HCC diagnosis, and the last clinical visit. Of 238 patients with SVR, HCC developed in 16 (6.8%) patients. The average follow-up period was 9.1 years. The cumulative incidence of HCC was 3.4% at 5 years and 7.5% at 10 years. The median pre-Tx and post-Tx WFA+-M2BP values were 1.69 (range: 0.28 to 12.04 cutoff index (COI)) and 0.80 (range: 0.17 to 5.29 COI), respectively. The WFA+-M2BP values decreased significantly after SVR (P < 0.001). The median post-Tx WFA+-M2BP value in patients who developed HCC was significantly higher than that in patients who did not (P < 0.01). Multivariate analysis disclosed that age (> 60 years), sex (male), pre-Tx platelet count (< 15.0×103/μL), and post-Tx WFA+-M2BP (> 2.0 COI) were associated with the development of HCC after SVR.ConclusionPost-Tx WFA+-M2BP (> 2.0 COI) is associated with the risk for development of HCC among patients with SVR. The WFA+-M2BP values could be a new predictor for HCC after SVR.

Homology between ABH-carrier α2-seminoglycoprotein and Mac-2 binding protein

α2-seminoglycoprotein (α2-SGP), purified from human seminal plasma, is a carrier of glycoprotein for the ABO blood grouping. The α2-SGP exists in the secretions of the seminal vesicle and various glands. However, the function of α2-SGP is, as yet, unknown. In this study, we determined that two internal amino acid sequences of 8 and 12 residues of α2-SGP were Ala-Val-Asp-Thr-Trp-Ser-Trp-Gly and Thr-Leu-Gln-Ala-Leu-Glu-Phe-His-Thr-Val-Pro-Phe. These sequences were completely coincident with the domain 3 of human Mac-2 binding protein (M2BP), which was identified as a tumor-associated antigen. In addition, we also confirmed an α2-SGP binding activity to galectin-3 that was one of a ligand for M2BP, and the immunological cross-reactivity between α2-SGP and M2BP. These findings strongly suggested that α2-SGP was identical with M2BP.

Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo.

Mouse cyclophilin C-associated protein (CyCAP) is a member of the scavenger-receptor cysteine-rich domain superfamily and is 69% identical to the human Mac-2 binding protein. Here, we show that CyCAP is a widely expressed secreted glycoprotein that modulates the host response to endotoxin. Gene-targeted CyCAP-deficient mice are more sensitive to the lethal effects of endotoxin. In response to endotoxin, CyCAP-deficient mice overproduced interleukin 12 and interferon-gamma systemically and tumor necrosis factor alpha locally; these are proinflammatory molecules that also promote T helper 1 responses. Furthermore, macrophages stimulated in vitro with endotoxin in serum deficient in CyCAP secreted more tumor necrosis factor alpha, supporting the proposal that CyCAP specifically down-modulates endotoxin signaling.

Mac-2 binding protein is a cell-adhesive protein of the extracellular matrix which self-assembles into ring-like structures and binds beta1 integrins, collagens and fibronectin.

Human Mac-2 binding protein (M2BP) was prepared in recombinant form from the culture medium of 293 kidney cells and consisted of a 92 kDa subunit. The protein was obtained in a native state as indicated by CD spectroscopy, demonstrating alpha-helical and beta-type structure, and by protease resistance and immunological analysis. It was highly modified by N- and O-glycosylation but not by glycosaminoglycans. Ultracentrifugation showed non-covalent association into oligomers with molar masses of 1000-1500 kDa. Electron microscopy showed ring-like shapes with diameters of 30-40 nm. M2BP bound in solid-phase assays to collagens IV, V and VI, fibronectin and nidogen, but not to fibrillar collagens I and III or other basement membrane proteins. The protein also mediated adhesion of cell lines at comparable strength with laminin. Adhesion to M2BP was inhibited by antibodies to integrin beta1 subunits but not to alpha2 and alpha6 subunits, RGD peptide or lactose. This distinguishes cell adhesion of M2BP from that of laminin and excludes involvement of lactose-binding galectin-3. Immunological assays demonstrated variable secretion by cultured human cells of M2BP, which was detected in the extracellular matrix of several mouse tissues.