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The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance.

ABSTRACT: Glycosyltransferase enzyme GCNT3, has been proposed as a biomarker for prognosis in colorectal cancer (CRC). Our study goes in depth into the molecular basis of GCNT3 role in tumorigenesis and drug resistance, and it explores its potential role as biomarker in epithelial ovarian cancer (EOC). High levels of GCNT3 are associated with increased sensibility to 5-fluoracil in metastatic cells. Accordingly, GCNT3 re-expression leads to the gain of anti-carcinogenic cellular properties by reducing cell growth, invasion and by changing metabolic capacities. Integrated transcriptomic and proteomic analyses reveal that GCNT3 is linked to cellular cycle, mitosis and proliferation, response to drugs and metabolism pathways. The vascular epithelial growth factor A (VEGFA) arises as an attractive partner of GCNT3 functions in cell invasion and resistance. Finally, GCNT3 expression was analyzed in a cohort of 56 EOC patients followed by a meta-analysis of more than one thousand patients. This study reveals that GCNT3 might constitute a prognostic factor also in EOC, since its overexpression is associated with better clinical outcome and response to initial therapy. GCNT3 emerges as an essential glycosylation-related molecule in CRC and EOC progression, with potential interest as a predictive biomarker of response to chemotherapy.

SUBMITTER: Fernandez LP

PROVIDER: S-EPMC5981315 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance.

Fernández Lara P LP Sánchez-Martínez Ruth R Vargas Teodoro T Herranz Jesús J Martín-Hernández Roberto R Mendiola Marta M Hardisson David D Reglero Guillermo G Feliu Jaime J Redondo Andrés A Ramírez de Molina Ana A

Scientific reports 20180531 1

Glycosyltransferase enzyme GCNT3, has been proposed as a biomarker for prognosis in colorectal cancer (CRC). Our study goes in depth into the molecular basis of GCNT3 role in tumorigenesis and drug resistance, and it explores its potential role as biomarker in epithelial ovarian cancer (EOC). High levels of GCNT3 are associated with increased sensibility to 5-fluoracil in metastatic cells. Accordingly, GCNT3 re-expression leads to the gain of anti-carcinogenic cellular properties by reducing cel ...[more]

PMID: 29855486

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Project description:PurposeColon adenocarcinoma (COAD) is the most common type of colorectal cancer (CRC) and is associated with poor prognosis. Emerging evidence has demonstrated that glycosylation by long noncoding RNAs (lncRNAs) was associated with COAD progression. To date, however, the prognostic values of glycosyltransferase (GT)-related lncRNAs in COAD are still largely unknown.MethodsWe obtained the expression matrix of mRNAs and lncRNAs in COAD from The Cancer Genome Atlas (TCGA) database. Then, the univariate Cox regression analysis was conducted to identify 33 prognostic GT-related lncRNAs. Subsequently, LASSO and multivariate Cox regression analysis were performed, and 7 of 33 GT-related lncRNAs were selected to conduct a risk model. Gene set enrichment analysis (GSEA) was used to analyze gene signaling pathway enrichment of the risk model. ImmuCellAI, an online tool for estimating the abundance of immune cells, and correlation analysis were used to explore the tumor-infiltrating immune cells in COAD. Finally, the expression levels of seven lncRNAs were detected in colorectal cancer cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).ResultsA total of 1,140 GT-related lncRNAs were identified, and 7 COAD-specific GT-related lncRNAs (LINC02381, MIR210HG, AC009237.14, AC105219.1, ZEB1-AS1, AC002310.1, and AC020558.2) were selected to conduct a risk model. Patients were divided into high- and low-risk groups based on the median of risk score. The prognosis of the high-risk group was worse than that of the low-risk group, indicating the good reliability and specificity of our risk model. Additionally, a nomogram based on the risk score and clinical traits was built to help clinical decisions. GSEA showed that the risk model was significantly enriched in metabolism-related pathways. Immune infiltration analysis revealed that five types of immune cells were significantly different between groups, and two types of immune cells were negatively correlated with the risk score. Besides, we found that the expression levels of these seven lncRNAs in tumor cells were significantly higher than those in normal cells, which verified the feasibility of the risk model.ConclusionThe efficient risk model based on seven GT-related lncRNAs has prognostic potential for COAD, which may be novel biomarkers and therapeutic targets for COAD patients.

Project description:BackgroundPrimary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients.MethodsIn this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier.ResultsIn advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression.ConclusionsAs a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.

Dataset Information

The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance.

Publications

The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance.

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