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N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

ABSTRACT: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically. IMPLICATIONS: Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.

SUBMITTER: DelaCourt A

PROVIDER: S-EPMC8802325 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

DelaCourt Andrew A Black Alyson A Angel Peggi P Drake Richard R Hoshida Yujin Y Singal Amit A Lewin David D Taouli Bachir B Lewis Sara S Schwarz Myron M Fiel M Isabel MI Mehta Anand S AS

Molecular cancer research : MCR 20210811 11

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate th ...[more]

PMID: 34380744

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Project description:Background: Previous studies have shown that glycosylation of proteins ofen plays an important role in HCC. However, the potential mechanism of glycosylation in HCC has not been described systematically. Methods: We comprehensively evaluated the glycosylation patterns in HCC samples based on 43 glycosylation regulators, and annotated the modification patterns with the enrichment of immune cells and stromal cells. Considering the heterogeneity of HCC patients, the glycosylation score was constructed using single-sample gene set enrichment analysis (ssGSEA). We also explored the drugs that different HCC patients were sensitive to based on glycosylation mode and score. Results: We identified three glycosylation-regulated gene subtypes. By annotating the subtypes, it was found that the glycosylation regulated gene subtypes was highly matched with three immunophenotypes of HCC (immune-inflamed, immune-excluded, and immune-desert), regardless of the characteristics of immune cell infiltration or prognosis. Based on the characteristic genes of glycosylation-regulated gene subtypes, we constructed a glycosylation-related model, and found that glycosylation-related model was highly consistent with the glycosylation regulated gene subtypes. The glycosylation score that evaluates the glycosylation characteristics of a single HCC sample has high prognostic value, and the prognosis of patients with high glycosylation score is significantly worse. Interestingly, we found that the glycosylation score was closely related to tumor node metastasis (TNM) staging. By applying glycosylation-regulated gene subtypes and glycosylation score to explore the sensitivity of different patients to anticancer drugs, it was found that the sensitivity of Thapsigargin, Shikonin, Embelin and Epothilone. B was closely related to the glycosylation mode. Conclusion: This study reveals that the diversity of glycosylation patterns plays an important role in HCC. Therefore, evaluating the glycosylation patterns of patients with HCC will be helpful in identifying the characteristics of immune cell infiltration and selecting accurate treatment methods.

Project description:BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide, seriously affecting human community health and care. Emerging evidence has shown that aberrant glycosylation is associated with tumor progression and metastasis. However, the role of glycosylation-related genes in HCC has notbeen reported.MethodsWeighted gene coexpression network analysis and non-negative matrix factorization analysis were applied to identify functional modules and molecularm subtypes in HCC. The least absolute shrinkage and selection operator Cox regression was used to construct the glycosylation-related signature. The independent prognostic value of the risk model was confirmed and validated by systematic techniques, including principal component analysis, T-distributed random neighbor embedding analysis, Kaplan-Meier survival analysis, the ROC curve, multivariate Cox regression, the nomogram, and the calibration curve. The single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were evaluated by the immune microenvironment and potential biological processes. The quantitative real-time polymerase chain reaction and immunohistochemistry analysis were used to verify the expression of five genes.ResultsWe identified the glycosylation-related genes with bioinformatics analysis to construct and validate a five-gene signature for the prognosis of HCC patients. Patients with HCC in the high-risk group had a worse prognosis. The risk score could be an independent factor and was associated with clinical features, such as the grade and stage. The nomogram exhibited an accurate score that included the risk score and clinical parameters. The infiltration levels of antitumor cells were upregulated in the low-risk group, including B_cells, Mast_cells, neutrophils, NK_cells, and T_helper_cells. Moreover, glycosylation was more sensitive to immunotherapy, and may play a critical role in the metabolic processes of HCC, such as bile acid metabolism and fatty acid metabolism. In addition, the five-gene messenger RNA (mRNA) and protein expression were overexpressed in HCC cells and tissues.ConclusionsThe glycosylation-related signature is effective for prognostic recognition, immune efficacy evaluation, and substance metabolism in HCC, providing a novel insight for therapeutic target prediction and clinical decision-making.

Project description:Sorafenib is a multikinase inhibitor and is effective in treating hepatocellular carcinoma (HCC). However, it remains unknown whether sorafenib induces the alteration of protein glycosylation. The present study treated HCC MHCC97L and MHCC97H cells with a 50% inhibitory concentration of sorafenib. Following this treatment, alteration of protein glycosylation was detected using a lectin microarray. Compared with the controls, the binding capacity of glycoproteins extracted from sorafenib-treated HCC cells to the lectins Bauhinia purpurea lectin, Dolichos biflorus agglutinin, Euonymus europaeus lectin, Helix aspersa lectin, Helix pomatia lectin, Jacalin, Maclura pomifera lectin and Vicia villosa lectin were enhanced; while, the binding capacities to the lectins Caragana arborescens lectin, Lycopersicon esculentum lectin, Limulus polyphemus lectin, Maackia amurensis lecin I, Phaseolus vulgaris leucoagglutinin, Ricinus communis agglutinin 60, Sambucus nigra lectin and Solanum tuberosum lectin were reduced (spot intensity median/background intensity median ≥2, P<0.05). This difference in glycoprotein binding capacity indicates that cells treated with sorafenib could increase α-1,3GalNAc/Gal, β-1,3 Gal, GalNAcα-Ser/Thr(Tn) and α-GalNAc structures and decrease GlcNAc, sialic acid, tetra-antennary complex-type N-glycan and β-1,4Gal structures. These results were additionally confirmed by lectin blotting. Expression levels of signaling molecules including erythroblastosis 26-1 (Ets-1), extracellular signal-related kinases (ERK) and phosphorylated-ERK were measured by western blotting. There was a reduction in the expression of Ets-1 and ERK phosphorylation in sorafenib or 1,4-Diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene treated cells suggesting that sorafenib may reduce the expression levels of Ets-1 by blocking the Ras/Raf/mitogen activated protein kinase signaling pathway. In the present study, it was clear that sorafenib could inhibit the proliferation of HCC cells and alter protein glycosylation. The findings of this study may lead to providing a novel way of designing new anti-HCC drugs.

Dataset Information

N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

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N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

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