• gene signature
• large cell neuroendocrine carcinoma
• machine learning
• neuroendocrine transdifferentiation
• prognosis
• prostate cancer
• stemness

• Humans
• Machine Learning
• Male
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Disease Progression
• Prognosis
• Gene Expression Regulation, Neoplastic
• Animals
• Transcriptome
• Biomarkers, Tumor/genetics
• Mice
• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/pathology
• Gene Expression Profiling/methods
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology

• U01 CA224044 NCI NIH HHS
• PICT-RAICES-2021-III-A-00080 Agencia Nacional de Promoción de la Investigación el Desarrollo Tecnológico y la Innovación (ANPCyT)

• Gene signature
• Large Cell Neuroendocrine Carcinoma
• Machine Learning
• Neuroendocrine Transdifferentiation
• Prognosis
• Prostate Cancer
• Stemness

• U01 CA224044 NCI NIH HHS

• Eimeria
• Broiler
• Coccidiosis
• Intestinal health
• Methionine

• 6040-32000-080-000D Agricultural Research Service

• CDK1
• FN1
• HMGB proteins
• IGBPB3
• SERPINE1
• TYMS
• ZWINT
• neuroendocrine prostatic cancer
• transcriptional regulation

• Humans
• Male
• Adenocarcinoma/pathology
• Cell Line
• HMGB1 Protein/genetics
• HMGB1 Protein/metabolism
• HMGB2 Protein/genetics
• HMGB2 Protein/metabolism
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Transcription Factors

• PI18/01417and Fortalece FORT23/00010 Instituto de Salud Carlos III
• PID2021-124564OB-I00 Ministerio de Ciencia e Innovación
• cofunded PI18/01417, PID2021-124564OB-I00, ED431C 2020-08 The European Regional Development Fund-ERDF
• ED431C 2020-08 Xunta de Galicia

• biomarkers
• ceRNAs
• ceRNETs
• ceRNome
• circRNAs
• lncRNAs
• microRNAs
• therapeutic targets
• triple-negative breast cancer (TNBC)

• 5-Fluorouracil
• Cancer stem cells
• Chemoresistance
• Colon cancer
• Manuka honey
• Spheroids

• Sp1
• TK1
• TYMS
• bioinformatics analysis
• miR-26b-5p
• uterine leiomyosarcoma

• Intratumoral heterogeneity
• Metastasis
• Microenvironment
• Osteosarcoma
• Recurrence
• Sequencing
• Single-cell

In recent years, the incidence and mortality of cervical cancer have increased worldwide. At the same time, increasing data have confirmed that miRNA-mRNA plays a positive or negative regulatory role in many cancers. This study attempted to screen effective miRNA-mRNA in the progression of cervical cancer, and to study the mechanism of miRNA-mRNA in the progression of cervical cancer. The expression profile data of GSE7410, GSE 63514, GSE 86100 and TCGA-CESC were downloaded, and 34 overlapping differentially expressed genes (22 up-regulated and 12 down-regulated) and 166 miRNAs (74 down-regulated and 92 up-regulated) were screened through limma package. Then, miR-197-3p/TYMS pairs were obtained by PPI, functional enrichment, Kaplan-Meier plotter analysis, Cox univariate and multivariate analysis, risk modeling, WGCNA, qPCR and dual-luciferase experiments. The results showed that TYMS was an independent prognostic factor of cervical cancer, and its expression level was negatively correlated with cervical cancer tissue grade (TMN), tumor grade, age, microsatellite stability and tumor mutation load, and positively correlated with methyl expression in DNMT1, DNMT2, DNMT3A and DNMT3B. Functional experiments showed that TYMS knockout could promote the proliferation, migration and invasion of HeLa cells and reduce apoptosis. Overexpression of TYMS showed the opposite trend, miR-197-3p was negatively correlated with the expression of TYMS. MiR-197-3p inhibitor reversed the effect of si-TYMS on the proliferation of HeLa cells. In conclusion, these results reveal that TYMS plays a very important role in the prognosis and progression of cervical cancer, and has the potential to be thought of as cervical cancer biomarkers. At the same time, miR-197-3p/TYMS axis can regulate the deterioration of cervical cancer cells, which lays a foundation for the molecular diagnosis and treatment of cervical cancer.

• apoptosis
• cervical cancer
• invasion and migration
• miR-197-3p/TYMS
• proliferation

• ferroptosis
• gene index
• immunotherapy
• prognosis
• prostate cancer

• Biomarkers, Tumor
• DNA Copy Number Variations
• Ferroptosis
• Humans
• Immunotherapy
• Male
• Prognosis
• Prostatic Neoplasms

• National Natural Science Foundation of China
• Postdoctoral Research Foundation of China
• Science and Technology Planning Project of Shenzhen Municipality
• Natural Science Foundation of Guangdong Province

• Adenocarcinoma of lung
• DNA repair
• prognosis
• transcriptome

• breast cancer
• diagnosis
• prognosis
• thymidylate synthase

• Thymidylate Synthase/genetics
• Thymidylate Synthase/metabolism
• Humans
• Female
• Prognosis
• Breast Neoplasms/pathology
• Breast Neoplasms/diagnosis
• Breast Neoplasms/genetics
• Breast Neoplasms/enzymology
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/diagnosis
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/enzymology
• Middle Aged
• Gene Expression Regulation, Enzymologic

• National Natural Science Foundation Of China

• HAPLN1
• IGFBP5
• TYMS
• autoantibody
• canine mammary tumour
• serum

• Colon cancer
• Dihydropyrimidine dehydrogenase
• Gene expression
• Real-time reverse-transcription polymerase chain reaction
• Thymidine phosphorylase
• Thymidylate synthase

• Colonic Neoplasms/metabolism
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil
• Humans
• Pyrimidines/metabolism
• Thymidylate Synthase

Retroperitoneal liposarcoma (RLPS) is one of the most common types of retroperitoneal sarcomas, and has a high recurrence rate. There is an urgent need to further explore its pathogenesis and develop more effective treatment strategies. The aim of the present study was to identify potential driver genes of RLPS through bioinformatics analysis and molecular biology to elucidate potential targets that are suitable for further analysis for the treatment of RLPS. Differentially expressed genes (DEGs) between liposarcoma and normal fatty (NF) tissues were identified based on microarray data through bioinformatics analysis, and thymidylate synthase (TYMS) was selected from the DEGs, based on high content screening (HCS). TYMS expression was evaluated in RLPS tumor tissues and cell lines. A total of 21 RLPS tissues and 10 NF frozen tissues were used for reverse transcription-quantitative PCR, and 47 RLPS formalin-fixed specimens were used for immunohistochemical analysis. The effect of TYMS downregulation on cell proliferation, apoptosis, cell cycle progression, and cell migration and invasion were evaluated using lentivirus-mediated short hairpin RNA. The underlying mechanisms of TYMS in RLPS were examined by protein microarray and verified by western blotting. A total of 855 DEGs were identified. TYMS knockdown had the most notable effect on the proliferative capacity of RLPS cells according to the HCS results. TYMS mRNA expression levels were higher in RLPS tissues compared with NF tissues (P<0.001). TYMS expression was higher in high-grade RLPS tissues compared with low-grade RLPS tissues (P=0.003). The patients with positive TYMS expression had a worse overall survival (OS) and disease-free survival (DFS) compared with the patients with negative TYMS expression (OS, P=0.024; DFS, P=0.030). The knockdown of TYMS reduced proliferation, promoted apoptosis, facilitated cell cycle progression from G₁ to S phase, and reduced cell migration and invasion of RLPS cells. Protein microarray analysis and western blotting showed that the Janus Kinase/Signal transducers and activators of transcription pathway was downregulated following TYMS knockdown. In conclusion, TYMS expression is upregulated in RLPS tissues, and downregulation of TYMS reduces RLPS progression.

Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth.

In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins.

In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.

• Cancer
• Chemoresistance
• Epithelial-to-mesenchymal transition
• Pyrimidine metabolism

• diagnosis
• pancreatic cancer
• prognosis
• tyms

• Biomarkers, Tumor/metabolism
• Case-Control Studies
• China/epidemiology
• Female
• Humans
• Male
• Middle Aged
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• Prognosis
• Thymidylate Synthase/metabolism
• Up-Regulation

• Gene expression
• ING4
• Ingenuity pathways analysis
• Prostate cancer
• RNA-Seq

• Kaplan-Meier curve
• adrenocortical carcinoma
• bioinformatics
• biomarkers
• differentially expressed genes
• hub genes

• pediatric
• pancreaticobiliary maljunction
• gene expression

• Bile Duct Neoplasms/etiology
• Bile Ducts/abnormalities
• Carrier Proteins/genetics
• Case-Control Studies
• Child
• Child, Preschool
• Dilatation, Pathologic/complications
• Dilatation, Pathologic/congenital
• Female
• Fucosyltransferases/genetics
• Gallbladder Neoplasms/etiology
• Gene Expression Profiling
• Humans
• Infant
• Male
• Microarray Analysis
• Pancreatic Ducts/abnormalities
• Up-Regulation/genetics
• Galactoside 2-alpha-L-fucosyltransferase

• Big data
• Fanconi anemia
• Genomics
• Machine learning
• Mathematical models
• Signaling pathways

• Databases, Factual
• Fanconi Anemia/metabolism
• Fanconi Anemia/pathology
• Genomics
• Humans
• Machine Learning
• Phenotype
• Proteins/metabolism
• Signal Transduction

• SAF2017-88908-R MINECO
• PT17/0009/0006 ISCIII
• 813533 H2020 Marie Curie Innovative Training Network
• 676559 H2020
• H2020 Marie Curie Innovative Training Network

The present study investigated the expression of excision repair cross-complementing gene 1 (ERCC1) and thymidylate synthase (TYMS) in patients with colorectal cancer and the predictive value of chemotherapy. Eighty patients with colorectal cancer chemotherapy admitted to Binzhou Medical University Hospital from June 2013 to June 2015 were randomly selected, and 80 cancer tissues and 68 adjacent tissues were taken for analysis. RT-qPCR was used to detect ERCC1 as well as the expression level of TYMS. The relationship of the expression level with the chemotherapy efficacy, clinical pathology and survival time in colorectal cancer patients receiving standard chemotherapy, was compared. The expression of ERCC1 and TYMS mRNA in cancer tissues was significantly higher than that in the adjacent tissues (P<0.05). There was no correlation between ERCC1 mRNA expression, TYMS mRNA and clinicopathological features of colorectal cancer (P>0.05). The predictive effect of ERCC1 on colorectal cancer chemotherapy was 0.919 (95% CI, 0.862–0.976), P<0.001. The AUC of TYMS for predicting the efficacy of chemotherapy on colon cancer was 0.831 (95% CI, 0.735–0.926), and both had higher predictive values. The expression levels of ERCC1 and TYMS mRNA in 80 patients with colorectal cancer were divided into the low and high expression groups. The 3-year survival rate of patients in the low expression group was significantly higher than that in the high expression group, and the difference between the two groups was statistically significant (P<0.05). ERCC1 and TYMS had a high predictive value for the efficacy of chemotherapy in patients with colorectal cancer, and patients with lower expression of ERCC1 and TYMS had improved 3-year survival rates than patients with higher expression. Therefore, for patients with colorectal cancer, ERCC1 and TYMS can be used as predictors of the efficacy of chemotherapy.

• ERCC1
• chemotherapy
• colorectal cancer
• efficacy
• prognosis
• thymidylate synthase

Traditional antitumor drugs inhibit the proliferation and metastasis of tumour cells by restraining the replication and expression of DNA. These drugs are usually highly cytotoxic. They kill tumour cells while also cause damage to normal cells at the same time, especially the hematopoietic cells that divide vigorously. Patients are exposed to other serious situations such as a severe infection caused by a decrease in the number of white blood cells. Energy metabolism is an essential process for the survival of all cells, but differs greatly between normal cells and tumour cells in metabolic pathways and metabolic intermediates. Whether this difference could be used as new therapeutic target while reducing damage to normal tissues is the topic of this paper. In this paper, we introduce five major metabolic intermediates in detail, including acetyl-CoA, SAM, FAD, NAD⁺ and THF. Their contents and functions in tumour cells and normal cells are significantly different. And the possible regulatory mechanisms that lead to these differences are proposed carefully. It is hoped that the key enzymes in these regulatory pathways could be used as new targets for tumour therapy.

• FAD
• NAD+
• SAM
• THF
• acetyl-CoA
• cancer

• canine mammary tumor
• collagen type II alpha 1 chain
• insulin-like growth factor-binding protein 5
• isobaric tags for relative and absolute quantification (iTRAQ)
• thymidylate synthetase

Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression at the protein levels in CCA tissues. In agreement, RT-qPCR and western blot analyses of four human CCA cell lines at the baseline level and in response to high doses of 5-FU revealed good correlations between FOXM1 and TYMS expression in the CCA cell lines tested, except for the highly 5-FU-resistant HuCCA cells. Consistently, siRNA-mediated knockdown of FOXM1 reduced the clonogenicity and TYMS expression in the relatively sensitive KKU-D131 but not in the highly resistant HuCCA cells. Interestingly, silencing of TYMS sensitized both KKU-D131 and HuCCA to 5-FU treatment, suggesting that resistance to very high levels of 5-FU is due to the inability of the genotoxic sensor FOXM1 to modulate TYMS expression. Consistently, ChIP analysis revealed that FOXM1 binds efficiently to the TYMS promoter and modulates TYMS expression at the promoter level upon 5-FU treatment in KKU-D131 but not in HuCCA cells. In addition, E2F1 expression did not correlate with either FOXM1 or TYMS expression and E2F1 depletion has no effects on the clonogenicity and TYMS expression in the CCA cells. In conclusion, our data show that FOXM1 regulates TYMS expression to modulate 5-FU resistance in CCA and that severe 5-FU resistance can be caused by the uncoupling of the regulation of TYMS by FOXM1. Our findings suggest that the FOXM1–TYMS axis can be a novel diagnostic, predictive and prognostic marker as well as a therapeutic target for CCA.

• Cholesterol
• Fatty acid
• Metabolism
• Prostate cancer

• #PCSM
• #ProstateCancer
• AdnaTest®
• circulating tumour cells
• epithelial mesenchymal transition
• prostate cancer
• stem cell

FAM13C, a gene with unknown function is included in several mRNA signatures for prostate cancer aggressiveness. To understand the impact of FAM13C on prognosis and its relationship to molecularly defined subsets, we analyzed FAM13C expression by immunohistochemistry on a tissue microarray containing 12,400 prostate cancer specimens. Results were compared to phenotype, ERG status, genomic deletions of 3p, 5q, 6q and PTEN, and biochemical recurrence. FAM13C was detectable in cell nuclei of cancerous and non-neoplastic prostate cells. 67.5% of 9,633 interpretable cancers showed FAM13C expression: strong in 28.3%, moderate in 24.6% and weak in 14.6%. Strong FAM13C expression was linked to advanced pT stage, high Gleason grade, positive lymph node status, and early biochemical recurrence (p < 0.0001 each). FAM13C expression was associated with TMPRSS2:ERG fusions. It was present in 85% of ERG positive but in only 54% of ERG negative cancers (p < 0.0001), and in 91.1% of PTEN deleted but in only 69.2% of PTEN non-deleted cancers (p < 0.0001). The prognostic role of FAM13C expression was independent of classical and quantitative Gleason grade, pT stage, pN stage, surgical margin status and preoperative PSA. In conclusion, the results of our study demonstrate that expression of FAM13C is an independent prognostic marker in prostate cancer. Finding FAM13C also in non-neoplastic prostate tissues highlights the importance of properly selecting cancer-rich areas for RNA-based FAM13C expression analysis.

• FAM13C
• immunohistochemistry
• prognosis
• prostate cancer

To investigate the association between 16 insertion-deletions (INDEL) polymorphisms, colorectal cancer (CRC) risk and clinical features in an admixed population.

One hundred and forty patients with CRC and 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. Clinicopathological data were obtained by consulting the patients’ clinical charts, intra-operative documentation, and pathology scoring.

Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis (TNM) stage risk, the Ins alleles of ACE, HLAG and TP53 (6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.

The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.

• Colorectal cancer
• Ins-del polymorphism
• Admixed population
• Potential biomarker
• Diagnostic
• Risk stratification
• Prognostic
• Clinical features

• Adult
• Aged
• Aged, 80 and over
• Brazil/epidemiology
• Case-Control Studies
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Electrophoresis, Capillary
• Female
• Genetic Predisposition to Disease
• Genotype
• Genotyping Techniques/instrumentation
• Genotyping Techniques/methods
• Humans
• INDEL Mutation/genetics
• Incidence
• Male
• Middle Aged
• Polymorphism, Genetic/genetics
• Risk Factors

Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to uncover the aberrant expression of metabolic enzymes in poorly-differentiated human hepatocellular carcinoma (HCC) for revealing targets against HCC malignancy. A total of 135 upregulated (22 are rate-limiting enzymes (RLEs)) and 362 down-regulated (77 are RLEs) metabolic genes were identified and associated with poor patient survival in large-cohorts of HCC patients in TCGA-LIHC and two other independent transcriptomic studies. Ten out of 22 upregulated RLEs in poorly-differentiated HCC are critical enzymes in pyrimidine metabolism pathways in association with stemness features by gene enrichment analysis and upregulated in ALDH1⁺ stem-like HCC subpopulations. By focusing on three RLEs including TK1, TYMS and DTYMK of dTTP biosynthesis pathway, expression of 3 RLEs in well-differentiated HCC cells increased ALDH1⁺ and spheroid stemness population but reversed by knockdown in poorly-differentiated HCC cells. Up-regulated 3 RLEs in HCC were associated with poor patient survival in multiple cohorts. Together, we identified aberrant pyrimidine pathway in poorly-differentiated HCC promotes cancer stemness served as potential theranostic target for battling HCC tumor progression.

• hepatocellular carcinoma
• poor differentiation
• pyrimidine metabolism
• rate-limiting enzymes
• stemness

• Gastric cancer
• Individualized treatment
• STMN1
• TUBB3
• TYMS
• UGT1A1 polymorphism

• Animals
• Cell Cycle/drug effects
• Cell Cycle/physiology
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/physiology
• Genes, Neoplasm/physiology
• Glycine N-Methyltransferase/metabolism
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Polymerase Chain Reaction
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/physiopathology
• Sarcosine/metabolism
• Sarcosine/pharmacology
• Sarcosine Dehydrogenase/metabolism
• Transcriptome
• Up-Regulation

• Grantová Agentura České Republiky
• CEITEC

Aberrant DNA methylation at promoters is often linked to tumorigenesis. But many aspects of DNA methylation remain unexplored, including the individual roles of distal and gene body methylation, as well as their collaborative roles with promoter methylation. Here we performed a MBD-seq analysis on prostate specimens classified into low, high, and very high risk group based on Gleason score and TNM stages. We identified gene sets with differential methylation regions (DMRs) in Distal, TSS, gene body and TES. To understand the collaborative roles, TSS was compared with the other three DMRs, resulted in 12 groups of genes with collaborative differential methylation patterns (CDMPs). We found several groups of genes that show opposite methylation patterns in Distal and Genic regions compared to TSS region, and in general they are differentially expressed genes (DEGs) in tumors in TCGA RNA-seq data. IPA (Ingenuity Pathway Analysis) reveals AR/TP53 signaling network to be a major signaling pathway, and survival analysis indicates genes subsets significantly associated with prostate cancer recurrence. Our results suggest that DNA methylation in Distal and Genic regions also plays critical roles in contributing to prostate tumorigenesis, and may act either positively or negatively with TSSs to alter gene regulation in tumors.

• Prostate biopsy
• Prostate cancer

• TAS-102
• antiangiogenesis
• colorectal cancer
• fluoropyrimidine resistance
• fluoropyrimidines
• trifluorothymidine