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The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their
Dong Gui Hu1, Shashikanth Marri2, Peter I Mackenzie1
1Dicipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia.
Abstract:
The human UDP-glycosyltransferase (UGTs) superfamily has 22 functional enzymes that play a critical role in the metabolism of small lipophilic compounds, including carcinogens, drugs, steroids, lipids, fatty acids, and bile acids. The expression profiles of UGT genes in human cancers and their impact on cancer patient survival remains to be systematically investigated. In the present study, a comprehensive analysis of the RNAseq and clinical datasets of 9514 patients from 33 different TCGA (the Genome Cancer Atlas) cancers demonstrated cancer-specific UGT expression profiles with high interindividual variability among and within individual cancers. Notably, cancers derived from drug metabolizing tissues (liver, kidney, gut, pancreas) expressed the largest number of UGT genes (COAD, KIRC, KIRP, LIHC, PAAD); six UGT genes (1A6, 1A9, 1A10, 2A3, 2B7, UGT8) showed high expression in five or more different cancers. Kaplan-Meier plots and logrank tests revealed that six UGT genes were significantly associated with increased overall survival (OS) rates [UGT1A1 (LUSC), UGT1A6 (ACC), UGT1A7 (ACC), UGT2A3 (KIRC), UGT2B15 (BLCA, SKCM)] or decreased OS rates [UGT2B15 (LGG), UGT8 (UVM)] in specific cancers. Finally, differential expression analysis of 611 patients from 12 TCGA cancers identified 16 UGT genes (1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2A3, 2B4, 2B7, 2B11, 2B15, 3A1, 3A2, UGT8) that were up/downregulated in at least one cancer relative to normal tissues. In conclusion, our data show widespread expression of UGT genes in cancers, highlighting the capacity for intratumoural drug metabolism through the UGT conjugation pathway. The data also suggests the potentials for specific UGT genes to serve as prognostic biomarkers or therapeutic targets in cancers.
Insights
This study reveals widespread UDP-glycosyltransferase (UGT) gene expression in human cancers, with specific UGTs showing potential as prognostic biomarkers or therapeutic targets for improved cancer patient survival.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Pharmacogenomics
Background:
- The UDP-glycosyltransferase (UGT) superfamily comprises 22 functional enzymes crucial for metabolizing lipophilic compounds like drugs, steroids, and carcinogens.
- Systematic investigation of UGT gene expression profiles in human cancers and their correlation with patient survival is lacking.
Purpose of the Study:
- To comprehensively analyze UGT gene expression across various human cancers using The Cancer Genome Atlas (TCGA) data.
- To determine the association between UGT gene expression and overall survival (OS) in cancer patients.
- To identify differentially expressed UGT genes in tumors compared to normal tissues.
Main Methods:
- Analysis of RNA sequencing and clinical data from 9514 patients across 33 TCGA cancer types.
- Utilized Kaplan-Meier plots and logrank tests to assess the association between UGT expression and OS.
- Differential expression analysis was performed on 611 patients from 12 TCGA cancers.
Main Results:
- Cancer-specific UGT expression profiles with significant interindividual variability were observed.
- Cancers from drug-metabolizing tissues (liver, kidney, gut, pancreas) exhibited the highest number of UGT genes.
- Six UGT genes (UGT1A1, UGT1A6, UGT1A7, UGT2A3, UGT2B15, UGT8) were significantly associated with patient OS in specific cancers.
- Six UGT genes demonstrated high expression in five or more cancer types.
- Six UGT genes were linked to increased OS (UGT1A1, UGT1A6, UGT1A7, UGT2A3, UGT2B15) or decreased OS (UGT2B15, UGT8) in specific cancers.
- Sixteen UGT genes were found to be differentially expressed (up/downregulated) in at least one cancer type compared to normal tissues.
Conclusions:
- Widespread expression of UGT genes in cancers indicates potential for intratumoral drug metabolism via the UGT conjugation pathway.
- Specific UGT genes may serve as valuable prognostic biomarkers for cancer patients.
- Targeting specific UGT genes presents a potential therapeutic strategy in cancer treatment.
