scholarly journals The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4491
Author(s):  
Dong Gui Hu ◽  
Shashikanth Marri ◽  
Peter I. Mackenzie ◽  
Julie-Ann Hulin ◽  
Ross A. McKinnon ◽  
...  

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.

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3369
Author(s):  
Dong Gui Hu ◽  
Peter I. Mackenzie ◽  
Pramod C. Nair ◽  
Ross A. McKinnon ◽  
Robyn Meech

ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.


2021 ◽  
Vol 12 ◽  
Author(s):  
Guojun Lu ◽  
Ying Zhou ◽  
Chenxi Zhang ◽  
Yu Zhang

BackgroundProtein-coding gene LIM Domain Kinase 1 (LIMK1) is upregulated in various tumors and reported to promote tumor invasion and metastasis. However, the prognostic values of LIMK1 and correlation with immune infiltrates in lung adenocarcinoma are still not understood. Therefore, we evaluated the prognostic role of LIMK1 and its correlation with immune infiltrates in lung adenocarcinoma.MethodsTranscriptional expression profiles of LIMK1 between lung adenocarcinoma tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). The LIMK1 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas. Receiver operating characteristic (ROC) curve was used to differentiate lung adenocarcinoma from adjacent normal tissues. Kaplan-Meier method was conducted to assess the effect of LIMK1 on survival. Protein-protein interaction (PPI) networks were constructed by the STRING. Functional enrichment analyses were performed using the “ClusterProfiler” package. The relationship between LIMK1 mRNA expression and immune infiltrates was determined by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB).ResultsThe expression of LIMK1 in lung adenocarcinoma tissues was significantly upregulated than those in adjacent normal tissues. Increased LIMK1 mRNA expression was associated with lymph node metastases and high TNM stage. The ROC curve analysis showed that with a cutoff level of 4.908, the accuracy, sensitivity, and specificity for LIMK1 differentiate lung adenocarcinoma from adjacent controls were 69.5, 93.2, and 71.9%, respectively. Kaplan-Meier survival analysis showed lung adenocarcinoma patients with high- LIMK1 had a worse prognosis than those with low- LIMK1 (43.1 vs. 55.1 months, P = 0.028). Correlation analysis indicated LIMK1 mRNA expression was correlated with tumor purity and immune infiltrates.ConclusionUpregulated LIMK1 is significantly correlated with poor survival and immune infiltrates in lung adenocarcinoma. Our study suggests that LIMK1 can be used as a biomarker of poor prognosis and potential immune therapy target in lung adenocarcinoma.


PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7976 ◽  
Author(s):  
Yaozong Wang ◽  
Baorong Song ◽  
Leilei Zhu ◽  
Xia Zhang

Background Dysregulated long non-coding RNAs (lncRNAs) may serve as potential biomarkers of cancers including breast cancer (BRCA). This study aimed to identify lncRNAs with strong prognostic value for BRCA. Methods LncRNA expression profiles of 929 tissue samples were downloaded from TANRIC database. We performed differential expression analysis between paired BRCA and adjacent normal tissues. Survival analysis was used to identify lncRNAs with prognostic value. Univariate and multivariate Cox regression analyses were performed to confirm the independent prognostic value of potential lncRNAs. Dysregulated signaling pathways associated with lncRNA expression were evaluated using gene set enrichment analysis. Results We found that a total of 398 lncRNAs were significantly differentially expressed between BRCA and adjacent normal tissues (adjusted P value <= 0.0001 and |logFC| >= 1). Additionally, 381 potential lncRNAs were correlated Overall Survival (OS) (P value < 0.05). A total of 48 lncRNAs remained when differentially expressed lncRNAs overlapped with lncRNAs that had prognostic value. Among the 48 lncRNAs, one lncRNA (LINC01614) had stronger prognostic value and was highly expressed in BRCA tissues. LINC01614 expression was validated as an independent prognostic factor using univariate and multivariate analyses. Higher LINC01614 expression was observed in several molecular subgroups including estrogen receptors+, progesterone receptors+ and human epidermal growth factor receptor 2 (HER2)+ subgroup, respectively. Also, BRCA carrying one of four gene mutations had higher expression of LINC01614 including AOAH, CIT, HER2 and ODZ1. Higher expression of LINC01614 was positively correlated with several gene sets including TGF-β1 response, CDH1 signals and cell adhesion pathways. Conclusions A novel lncRNA LINC01614 was identified as a potential biomarker for prognosis prediction of BRCA. This study emphasized the importance of LINC01614 and further research should be focused on it.


2020 ◽  
Author(s):  
Shuangqing Cao ◽  
Lei Zheng

Abstract Background MicroRNA-138 (miR-138) is shown to inhibit tumor growth and played a critical role in tumor pathogenesis, the present study aimed to investigate the prognistic value of miR-138 in cervical cancer. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect the expression of miR-138 in the tissues of cervical cancer and adjacent normal tissues. The association of miR-138 expression with clinical characteristic was analyzed via χ2 test. Then Kaplan-Meier analysis was performed to analyze the association of miR-138 expression with the overall survival of cervical cancer patients. The multivariate cox analysis was used to evaluate the prognostic value of miR-138. Results In the current study, we found the expression level of miR-138 was significantly downregulated in the most cervical cancer patients tissues compared with that in the adjacent normal tissues (P < 0.001). And its expression was closely affected by TNM stage (P = 0.043), lymph node metastasis (P = 0.011) and FIGO stage (P = 0.002). Kaplan-Meier analysis result showed that the decreased expression level of miR-138 expression was associated with poor overall survival of patients. The cox regression analysis result indicated that miR-138 expression was independently associated with the overall survival. Conclusions The expression of miR-138 is down-regulated and involved in the development of cervical cancer. Moreover, it may serve as a prognostic marker for patients with cervical cancer.


2021 ◽  
Author(s):  
Yongjie Li ◽  
Min Zeng ◽  
Ting Wang ◽  
Feng Jiang

Abstract Background Pancreatic cancer is a malignant tumor of digestive system with high fatality rate, and its prognosis is very poor. Type Ⅴ collagen α3 (COL5A3) is highly expressed in a variety of tumor tissues, but its prognostic value and immune infiltration in pancreatic cancer are still unclear. Therefore, we evaluated the prognostic role of COL5A3 in pancreatic cancer and its correlation with immune infiltration. Methods The transcriptional expression profiles of COL5A3 in pancreatic cancer and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). In the GEO (Gene expression omnibus) dataset (GSE16515), we compared the expression of COL5A3 in normal and tumor tissues. The expression of COL5A3 protein was evaluated by the human protein atlas (THPA). The effect of COL5A3 on survival was evaluated by Kaplan-Meier method. Receiver operating characteristic (ROC) curve was used to distinguish pancreatic cancer from paracancerous normal tissues. Protein-protein interaction (PPI) network was constructed by the STRING. Use the "ClusterProfiler" package for functional enrichment analysis. Tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB) were used to determine the relationship between COL5A3mRNA expression and immune infiltration. Results Compared with normal tissues, COL5A3 is highly expressed in pancreatic cancer tissues. The high expression of COL5A3 is related to the poor clinicopathological features and poor prognosis of pancreatic cancer. Kaplan-Meier survival analysis showed that the prognosis of pancreatic cancer patients with high expression of COL5A3 was worse than that of patients with low expression of COL5A3. ROC curve shows that COL5A3 has high sensitivity and specificity in the diagnosis of pancreatic cancer. Correlation analysis showed that the expression of COL5A3mRNA was related to immune cell infiltration. Conclusion This study reveals for the first time that COL5A3 may be a new prognostic biomarker related to immune infiltration and provide a new target for the diagnosis and treatment of pancreatic cancer.


2021 ◽  
Vol 8 (3) ◽  
pp. 21-33
Author(s):  
A. A. Pushkin ◽  
E. A. Dzenkova ◽  
N. N. Timoshkina ◽  
D. Yu. Gvaldin

Purpose of the study. This research was devoted to study of mRNA and miRNA expression patterns in glioglastomas using The Cancer Genome Atlas (TCGA) data, to search for genetic determinants that determine the prognosis of patient survival and to create of interaction networks for glioblastomas.Materials and methods. Based on the data of the open TCGA database groups of glioblastomas and conventionally normal brain tissue samples were formed. Survival gene and miRNA expression data were extracted for each sample. After the data stratification by groups the differential expression analysis and search the genes affecting patient survival was carried out. The enrichment analysis by functional affiliation and an interactome analysis were performed.Results. A total of 156 glioblastoma samples with mRNA sequencing data, 571 samples with microarray microRNA analysis data, and 15 control samples were analyzed. Networks of mRNA-miRNA interactions were built and expression profiles of genes and miRNAs characteristic of glioblastomas were developed. We have determined the genes which aberrant level is associated with survival and shown the pairwise DEG and DE of microRNA correlations.Conclusion. The microRNA-mRNA regulatory pairs identified for glioblastomas can stimulate the development of new therapeutic approaches based on subtype-specific regulatory mechanisms of oncogenesis.


2021 ◽  
Author(s):  
Min Wang ◽  
Tao Lu ◽  
Yanshi Li ◽  
Min Pan ◽  
Zhihai Wang ◽  
...  

Abstract Background: Head and neck cancer (HNC) are highly aggressive solid tumors with poor prognoses. The tumor microenvironment (TME) plays a critical role in angiogenesis, invasion, and metastasis of HNC. In the TME, immune and stromal cells influence tumor initiation, response, and therapy. Our study aimed to evaluate the progression and prognosis of HNC by analyzing the key genes involved in immunization and stromal cells. Methods: Gene expression profiles, demographics, and survival data were downloaded from the TCGA database. Patients with HNC were divided into high immune/stromal score groupss or low immune/stromal score groups based on the ESTIMATE algorithm. Differentially expressed genes (DEGs) were identified via functional enrichment analysis and protein-protein interaction networks, and survival analysis based on DEGs was also performed.Results: A total of 522 patients with HNC were enrolled for analysis. The average age was 60.87, and one-third of the patients were HPV-positive. Kaplan-Meier survival analysis showed that patients' median survival time in the low-score group was shorter than that of the high-score group (625 vs. 680 days, log-rank, p = 0.1716). According to immune scores, 925 genes were upregulated, and 72 genes were downregulated in the high-score group compared with the low-score group. Top Gene Ontology terms identified that T-cell costimulation, regulation of immune response, and the external side of the plasma membrane were the most involved pathways. Moreover, Kaplan-Meier analysis revealed that 480 DEGs were upregulated in the high-immune scores group, and a total of 126 DEGs were significantly associated with poor survival. Besides, we identified the hub genes of DEGs through protein-protein interactions and found that PTPRC, CD247, and CD4 are associated with immune infiltration and all-cause mortality.Conclusions: We identified a series of TME‐related genes significantly associated with overall mortality; this information is crucial for further understanding the role of TME and immune infiltration in the prognosis of HNC.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaonan Liu ◽  
Pei Wang ◽  
Xufei Teng ◽  
Zhang Zhang ◽  
Shuhui Song

BackgroundN6-methyladenosine (m6A), the most abundant chemical modification on eukaryotic messenger RNA (mRNA), is modulated by three class of regulators namely “writers,” “erasers,” and “readers.” Increasing studies have shown that aberrant expression of m6A regulators plays broad roles in tumorigenesis and progression. However, it is largely unknown regarding the expression regulation for RNA m6A regulators in human cancers.ResultsHere we characterized the expression profiles of RNA m6A regulators in 13 cancer types with The Cancer Genome Atlas (TCGA) data. We showed that METTL14, FTO, and ALKBH5 were down-regulated in most cancers, whereas YTHDF1 and IGF2BP3 were up-regulated in 12 cancer types except for thyroid carcinoma (THCA). Survival analysis further revealed that low expression of several m6A regulators displayed longer overall survival times. Then, we analyzed microRNA (miRNA)-regulated and DNA methylation-regulated expression changes of m6A regulators in pan-cancer. In total, we identified 158 miRNAs and 58 DNA methylation probes (DMPs) involved in expression regulation for RNA m6A regulators. Furthermore, we assessed the survival significance of those regulatory pairs. Among them, 10 miRNAs and 7 DMPs may promote cancer initiation and progression; conversely, 3 miRNA/mRNA pairs in kidney renal clear cell carcinoma (KIRC) may exert tumor-suppressor function. These findings are indicative of their potential prognostic values. Finally, we validated two of those miRNA/mRNA pairs (hsa-miR-1307-3p/METTL14 and hsa-miR-204-5p/IGF2BP3) that could serve a critical role for potential clinical application in KIRC patients.ConclusionsOur findings highlighted the importance of upstream regulation (miRNA and DNA methylation) governing m6A regulators’ expression in pan-cancer. As a result, we identified several informative regulatory pairs for prognostic stratification. Thus, our study provides new insights into molecular mechanisms of m6A modification in human cancers.


PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7946 ◽  
Author(s):  
Shuming Zhang ◽  
Shichao Guo ◽  
Zhangfu Li ◽  
Dan Li ◽  
Qimin Zhan

Background Heat shock protein 90 (HSP90) is a highly conserved chaperone with an approximate molecular weight of 90-kDa. It plays a critical role in maintaining stability and homeostasis of oncoproteins, helping cancer cells living in the unsuitable environmental conditions. The current study aims to inquire the difference of HSP90 expression in tumor tissues and normal tissues, analyze the correlation between HSP90 expression and the prognoses of patients with colorectal cancer (CRC), and investigate its role in CRC preliminarily. Methods Online analysis of HSP90 mRNA levels in different cancers was firstly done in Gene Expression Profiling Interactive Analysis. Then HSP90 expression was determined by immunohistochemistry between 99 CRC tissues and 81 normal tissues. Chi-square test or Fisher’s exact test was used to analyze the relationship between HSP90 and histopathologic characteristics. Kaplan–Meier analysis and Cox’s proportional hazards model were also done for further analysis of the prognostic values of HSP90. Pearson’s correlation coefficients between HSP90 expression values and other mRNA expression values were calculated based on The Cancer Genome Atlas dataset and bioinformatic analysis was done about these screened genes. Results Colorectal cancer tissues showed significantly higher expression of HSP90 than normal tissues (55.6% vs. 3.7%, P < 0.0001). Kaplan–Meier curves showed high HSP90 expression was associated with poor prognosis (P = 0.039) in CRC patients, and multivariate Cox proportional hazards regression model analysis also indicated that HSP90 expression (HR = 1.930, 95% CI [1.113–3.349], P = 0.019) linked to poor prognosis. Moreover, 85 genes were correlated with HSP90, which were involved in metabolic process and enriched in pathways of Proteasome and Base excision repair. Conclusions Our results suggested that HSP90 expression is inversely associated with survival outcomes and could be an independent prognostic factor for CRC patients. It mainly involved in metabolic process and exerted binding and catalytic activities.


2021 ◽  
Author(s):  
Yongjie Li ◽  
Min Zeng ◽  
Ting Wang ◽  
Feng Jiang

Abstract Pancreatic cancer is a malignant tumor of digestive system with high fatality rate, and its prognosis is very poor. Type Ⅴ collagen α3 (COL5A3) is highly expressed in a variety of tumor tissues, but its prognostic value and immune infiltration in pancreatic cancer are still unclear. Therefore, we evaluated the prognostic role of COL5A3 in pancreatic cancer and its correlation with immune infiltration. The transcriptional expression profiles of COL5A3 in pancreatic cancer and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). In the GEO (Gene expression omnibus) dataset (GSE16515), we compared the expression of COL5A3 in normal and tumor tissues. The expression of COL5A3 protein was evaluated by the human protein atlas (THPA). The effect of COL5A3 on survival was evaluated by Kaplan-Meier method. Receiver operating characteristic (ROC) curve was used to distinguish pancreatic cancer from paracancerous normal tissues. Protein-protein interaction (PPI) network was constructed by the STRING. Use the "ClusterProfiler" package for functional enrichment analysis. Tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB) were used to determine the relationship between COL5A3 mRNA expression and immune infiltration. Compared with normal tissues, COL5A3 is highly expressed in pancreatic cancer tissues. The high expression of COL5A3 is related to the poor clinicopathological features and poor prognosis of pancreatic cancer. Kaplan-Meier survival analysis showed that the prognosis of pancreatic cancer patients with high expression of COL5A3 was worse than that of patients with low expression of COL5A3. ROC curve shows that COL5A3 has high sensitivity and specificity in the diagnosis of pancreatic cancer. Correlation analysis showed that the expression of COL5A3 mRNA was related to immune cell infiltration. This study reveals for the first time that COL5A3 may be a new prognostic biomarker related to immune infiltration and provide a new target for the diagnosis and treatment of pancreatic cancer.


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