Glycan and Glycosylation as a Target for Treatment of Glioblastoma

Glycosylation is an important post-translational modification regulating many cellular processes. In cancer, aberrant glycosylation leads to the expression of tumor-associated glycans that are possibly used as therapeutic targets or biomarkers for diagnosis, monitoring, and prognostic prediction. The cumulative evidence suggested the significance of alteration of glycosylation in glioblastoma (GBM). Aberrant glycosylation presents truncated or uncommon glycans on glycoproteins, glycolipids, and other glycoconjugates. These aberrant glycans consequently promote the tumor development, metastasis, and therapeutic resistance. The glycosylation changes occurred in either cancer cells or the tumor microenvironment. GBM-associated glycans and their corresponding enzymes are proposed to be a target for GBM treatment. Several tools, such as lectin and inhibitors, are possibly applied to target the tumor-associated glycans and glycosylation for the treatment of GBM. This chapter provides information insight into glycosylation changes and their roles in the development and progression of GBM. The perspectives on targeting glycans and glycosylation for the treatment of GBM are enclosed

Urinary metabolic profile and its predictive indexes after MSG consumption in rat

Monosodium glutamate (MSG) is a widely used food additive with conflicting evidence regarding its potential effects on human health, with proposed relevance for obesity and metabolic syndrome (MetS) or chronic kidney disease. As being able to accurately quantify the MSG dietary intake would help clarify the open issues, we constructed a predictive formula to estimate the daily intake of MSG in a rat model based on the urinary metabolic profile. Adult male Wistar rats were divided into groups receiving different daily amounts of MSG in drinking water (0.5, 1.5, and 3.0 g%), no MSG, and MSG withdrawal after 3.0% MSG treatment for 4 weeks. We then analyzed 24-hour urine samples for chemistries and metabolites using 1H NMR spectrometry and observed a strong correlation between urine pH, sodium, bicarbonate, alpha-ketoglutarate, citrate, fumarate, glutamate, methylamine, N-methyl-4-pyridone-3-carboxamide, succinate, and taurine and the daily MSG intake. Following the multiple linear regression analysis a simple formula model based on urinary Na+, citrate, and glutamate was most accurate and could be validated for estimating daily MSG intake. In conclusion, we propose that the daily MSG intake correlates with urinary metabolites in a rat model and that this new tool for monitoring the impact of MSG on health measures

Serum N-Glycomics with Nano-LC-QToF LC-MS/MS Reveals N-Glycan Biomarkers for Glioblastoma, Meningioma, and High-Grade Meningioma.

Alteration of glycosylation in cancer cells leads to the expression of tumor-associated glycans, which can be used as biomarkers for diagnosis and prognostic prediction of diseases. In this study, we used nano-LC-QToF to identify serum N-glycan biomarkers for the detection of brain tumors. We observed an increase in sialylated N-glycans and a decrease in fucosylated N-glycans in the serum of patients with glioblastoma (GBM) and meningioma (MG) compared to healthy individuals. In GBM, a combination of increased serum sialylated N-glycan (6_4_0_2 compound) and decreased fucosylated N-glycan (4_4_1_0 compound) was identified as the most appropriate panel, with an area under the curve (AUC) of 0.8660, 78.95% sensitivity, 84.21% specificity, and 82.89% accuracy. For MG, a combination of decreased 6_6_2_0 and 5_5_2_0 compounds and increased 4_4_1_1 compound achieved an AUC of 0.9260, 82.35% sensitivity, 78.57% specificity, and 80.26% accuracy for diagnosis of MG. Additionally, an increase in 5_5_1_0 and 4_3_0_0 compounds combined with a decrease in 7_7_4_3 was associated with high-grade MG (WHO grades II-III). In conclusion, we identified serum N-glycan profiles associated with brain tumors, highlighting their potential as biomarkers for the diagnosis and prognosis of these diseases

Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways

Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway.</jats:p

Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways

Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway

Carbohydrate Antigen 50: Values for Diagnosis and Prognostic Prediction of Intrahepatic Cholangiocarcinoma

Background and objectives: Cancer-associated carbohydrate antigen 50 (CA50) is a marker for detection of gastrointestinal cancers, especially of pancreatic and colon cancer. In this study, the power of CA50 as a diagnostic and prognostic marker was evaluated in intrahepatic cholangiocarcinoma (iCCA). Materials and Methods: Serum CA50 levels of iCCA patients and non-cholangiocarcinoma controls (non-CCA, including healthy persons and patients with benign biliary diseases and other gastrointestinal cancers) were measured using MAGLUMI®800 CLIA analyzer. Diagnostic and prognostic values of serum CA50 levels were evaluated. Results: CA50 levels in the sera of iCCA patients were significantly higher than those of non-CCA controls (p &lt; 0.001, Mann–Whitney U test). Using cut-off value of 25 U/mL, CA50 provided 65.9% sensitivity, 87.3% specificity, and 80.1% accuracy for diagnosis of iCCA. Serum CA50 levels were increased and associated with the severity of bile duct pathology. In addition, a higher level of CA50 was associated with poor clinical outcome and shorter survival in iCCA patients. Multivariate survival analysis by Cox regression model revealed the potential of CA50 as an independent poor prognostic indicator for iCCA, regardless of the age, sex, histological types, or tumor stages. Conclusions: CA50 can be a diagnostic and poor prognostic marker candidate for iCCA.</jats:p