Potential of Mac-2-binding protein glycan isomer as a new therapeutic target in pancreatic cancer.

Pancreatic cancer (PC) is a challenging malignancy to treat. Mac-2-binding protein glycan isomer (M2BPGi) is a novel serum marker of liver fibrosis and hepatocellular carcinoma and is secreted by hepatic stellate and stroma cells. Serum M2BPGi levels are upregulated in PC patients. We measured the expression of M2BPGi in the serum of 27 PC patients and determined whether M2BPGi affects the malignant potential of PC cells in vitro. We also examined the effect of M2BP on PC tumor growth and gemcitabine sensitivity in vivo. Serum M2BPGi levels in PC patients were higher compared with those of healthy subjects. M2BPGi extraction in cancer-associated fibroblasts (CAFs) was higher compared with that of PC cells. M2BPGi treatment promoted the proliferation and invasion of PC cells. The suppression of galectin-3, which binds to M2BPGi, did not affect the proliferation-promoting effect of M2BPGi in PC cells. The suppression of M2BP reduced tumor growth and enhanced gemcitabine sensitivity in PC-bearing xenograft mice. CAF-derived M2BPGi promotes the proliferation and invasion of PC cells. Targeting M2BPGi may represent a new therapeutic strategy to circumvent refractory PC.

A new liver regeneration molecular mechanism involving hepatic stellate cells, Kupffer cells, and glucose-regulated protein 78 as a new hepatotrophic factor.

BACKGROUND/PURPOSE: To overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC-secreted Mac-2-binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC-derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration. METHODS: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins was examined in vitro and in murine hepatectomy models. RESULTS: Although M2BPGi had no hepatocyte-promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC-driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice. CONCLUSIONS: The M2BPGi-activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure.

Clinical implications of serum Mac-2-binding protein glycan isomer as a novel biomarker of advanced hepatic fibrosis in diabetes.

BACKGROUND: Appropriate strategy for screening, identification, and linkage to care of patients with advanced fibrosis in the general population is a current issue. The aim of this study was to find reference values and the clinical role of Mac-2 binding protein glycan isomer (M2BPGi) in a health check-up setting. METHODS: This study was designed as cross-sectional study. Adult subjects (n=1,073) who underwent a health check-up were included in the final analysis, and 952 subjects with risk factors for liver disease and insufficient data were excluded. M2BPGi quantification was based on a lectin antibody sandwich immunoassay. Fatty liver was diagnosed using abdominal sonography. RESULTS: The reference value of M2BPGi was 0.5-1.0 cut off index (COI) in the average risk group. Serum M2BPGi showed a positive correlation with metabolic parameters as well as age. Prevalence of abnormal M2BPGi (>1.0) was higher in low muscle mass (4.7%, vs. 17.4%, P=0.002), metabolic syndrome (14.2% vs. 30.4%, P=0.003), and hypertension (21.8%, vs. 58.7%, P<0.001) compared to healthy controls. M2BPGi was positively correlated with estimated fibrosis values such as FIB-4 (R=0.293, P<0.001) and NAFLD fibrosis score (R=0.248, P<0.001). Although the prevalence of advanced fibrosis in the total population was just 1.6% (FIB-4 >2.65), the prevalence of advanced fibrosis increased to 50% in the high M2BPGi (>1.0) group with diabetes. This value was 31.25 times higher than in the total population group. CONCLUSIONS: The results indicated a high possibility of advanced hepatic fibrosis in diabetic subjects with abnormal M2BPGi level (>1.0).

Novel biomarkers for the management of chronic hepatitis B.

Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.