• BER
• DNA damage
• DNA damage response
• DNA repair
• HR
• MMR
• NER
• NHEJ
• autoimmune diseases
• cancer
• genomic instability
• human diseases
• neurodegenerative disorders

• Humans
• Neurodegenerative Diseases/genetics
• DNA Repair/genetics
• Neoplasms/genetics
• DNA Damage/genetics
• Immune System Diseases/genetics
• Genome-Wide Association Study
• Genetic Predisposition to Disease
• Genomic Instability/genetics
• Polymorphism, Single Nucleotide

• LX22NPO5102 National Institute for Cancer Research

• chemotherapy
• colorectal cancer
• drug resistance
• immunotherapy
• resistance mechanisms
• targeted therapy
• therapeutic strategies

• Humans
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Tumor Microenvironment/drug effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Epigenesis, Genetic
• Signal Transduction/drug effects
• Molecular Targeted Therapy/methods
• Animals
• DNA Damage
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/drug effects

• Cancer biomarkers
• Cancer treatment
• DCLRE1C
• Non-homologous end joining
• Radiosensitization

• Aggressiveness
• Cancer
• Cancer prognosis and diagnosis
• Oncogene
• Precision oncology
• Tumor
• WNT pathway
• WNT6

• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/diagnosis
• Neoplasms/genetics
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Wnt Proteins/metabolism
• Animals
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins/genetics
• Wnt Signaling Pathway

• UIDB/50026/2020 Fundação para a Ciência e a Tecnologia
• UIDB/50026/2020 Fundação para a Ciência e a Tecnologia
• CEECIND/00072/2018/CP1581/CT0011 Fundação para a Ciência e a Tecnologia
• NORTE-01-0145-FEDER-000055 Norte Portugal Regional Operational Programme (NORTE 2020)
• NORTE-01-0145-FEDER-000055 Norte Portugal Regional Operational Programme (NORTE 2020)
• NORTE-01-0145-FEDER-000055 Norte Portugal Regional Operational Programme (NORTE 2020)

• 3D co-culture system
• Chemoresistance
• FOLFOX
• GTF2H5
• Synthetic lethality

• Colon cancer
• Epigenetic diagnosis
• Liquid biopsy
• Postoperative monitoring
• ctDNA

• Humans
• Colonic Neoplasms/genetics
• Colonic Neoplasms/diagnosis
• Colonic Neoplasms/blood
• DNA Methylation/genetics
• Circulating Tumor DNA/genetics
• Circulating Tumor DNA/blood
• Female
• Male
• Middle Aged
• Liquid Biopsy/methods
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/blood
• Aged
• Early Detection of Cancer/methods
• Epigenesis, Genetic
• Case-Control Studies
• Sensitivity and Specificity
• Cell-Free Nucleic Acids/genetics
• Cell-Free Nucleic Acids/blood
• Adult
• Prognosis

• Bioinformatics
• Colorectal cancer
• Epigenetic-related genes
• Prognosis
• Risk score

• Humans
• Prognosis
• Oncogenes
• Nomograms
• Epigenesis, Genetic
• Genetic Risk Score
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics

• Aging
• Base excision repair
• Bowhead
• NEIL1
• RNA editing

• autoantibodies
• autoimmunology
• biomarkers
• endometriosis
• peritoneal fluid
• plasma
• proteome microarray

Molecular analysis facilitates the prediction of overall survival (OS) of breast cancer and decision-making of the treatment plan. The current study was designed to identify new prognostic genes for breast cancer and construct an effective prognostic signature with integrated bioinformatics analysis. Differentially expressed genes in breast cancer samples from The Cancer Genome Atlas (TCGA) dataset were filtered by univariate Cox regression analysis. The prognostic model was optimized by the Akaike information criterion and further validated using the TCGA dataset (n = 1014) and Gene Expression Omnibus (GEO) dataset (n = 307). The correlation between the risk score and clinical information was assessed by univariate and multivariate Cox regression analyses. Functional pathways in relation to high-risk and low-risk groups were analyzed using gene set enrichment analysis (GSEA). Four prognostic genes (EXOC6, GPC6, PCK2, and NFATC2) were screened and used to construct a prognostic model, which showed robust performance in classifying the high-risk and low-risk groups. The risk score was significantly related to clinical features and OS. We identified 19 functional pathways significantly associated with the risk score. This study constructed a new prognostic model with a high prediction performance for breast cancer. The four-gene prognostic signature could serve as an effective tool to predict prognosis and assist the management of breast cancer patients.

Cancer driver gene is a type of gene with abnormal alterations that initiate or promote tumorigenesis. Driver genes can be used to reveal the fundamental pathological mechanisms of tumorigenesis. These genes may have pathological changes at different omics levels. Thus, identifying cancer driver genes involving two or more omics levels is essential. In this study, a computational investigation was conducted on lung cancer driver genes. Four omics levels, namely, epigenomics, genomics, transcriptomics, and post-transcriptomics, were involved. From the driver genes at each level, the Laplacian heat diffusion algorithm was executed on a protein–protein interaction network for discovering latent driver genes at this level. A following screen procedure was performed to extract essential driver genes, which contained three tests: permutation, association, and function tests, which can exclude false-positive genes and screen essential ones. Finally, the intersection operation was performed to obtain novel driver genes involving two omic levels. The analyses on obtained genes indicated that they were associated with fundamental pathological mechanisms of lung cancer at two corresponding omics levels.

The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.

• Wnt
• colorectal cancer
• therapeutic strategy
• β‑catenin

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/physiology
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Epithelial-Mesenchymal Transition/drug effects
• Gene Expression Regulation, Neoplastic
• Humans
• Molecular Targeted Therapy/methods
• Mutation
• RNA, Untranslated
• Wnt Signaling Pathway/drug effects
• beta Catenin/metabolism

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes’ single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

• DNA methylation
• biomarker
• cfDNA
• colorectal cancer
• liquid biopsy

• Biomarkers, Tumor
• Cell-Free Nucleic Acids
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Computational Biology/methods
• DNA Methylation
• DNA, Neoplasm
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Liquid Biopsy/methods
• Liquid Biopsy/standards
• Neoplasm Metastasis
• ROC Curve

• Astroprincin
• Colon cancer
• FAM171A1
• Immunohistochemistry
• Tissue microarray

• DNA damage response
• TP53 mutational status
• cancer progression
• cancer risk
• cancer therapy
• interactions
• telomere homeostasis

• 2,4,6-trinitrobenzenesulfonic acid (PubChem CID: 11045)
• AS605240 (PubChem CID: 5289247)
• Celiac disease
• Colorectal cancer
• Cytokines
• DAMGO (PubChem CID: 5462471)
• FR167653 (PubChem CID: 135484078)
• Inflammatory bowel disease
• Irritable bowel syndrome
• Mangiferin (PubChem CID: 5281647)
• NF-κB
• PD98059 (PubChem CID: 4713)
• Pyrrolidine dithiocarbamate (PubChem CID: 65351)
• SB203580 (PubChem CID: 176155)
• SP600125 (PubChem CID: 8515)
• XG-102 (PubChem CID: 90479374)

The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression.

• DNA damage
• DNA glycosylase
• DNA repair
• DNA-binding protein
• DNA–protein interaction
• GRF
• X-ray crystallography
• base excision repair (BER)
• crystallography
• interstrand DNA cross-link
• nucleic acid enzymology
• zinc finger

• Amino Acid Sequence
• Animals
• Crystallography, X-Ray
• DNA/metabolism
• DNA Replication
• DNA, Single-Stranded/chemistry
• DNA, Single-Stranded/metabolism
• Humans
• Mice
• N-Glycosyl Hydrolases/antagonists & inhibitors
• N-Glycosyl Hydrolases/genetics
• N-Glycosyl Hydrolases/metabolism
• Protein Binding
• Protein Structure, Tertiary
• Sequence Alignment
• Zinc Fingers

• P01 CA092584 NCI NIH HHS
• R01 GM131071 NIGMS NIH HHS
• R35 GM136401 NIGMS NIH HHS
• T32 GM008320 NIGMS NIH HHS
• HHS | NIH | National Institute of General Medical Sciences (NIGMS)
• HHS | NIH | National Cancer Institute (NCI)
• HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)
• NSF | EHR | Division of Graduate Education (DGE)

The study is aimed at investigating the role of Nei endonuclease VIII-like1 (NEIL1) in the pathogenesis of colorectal cancer (CRC). The human CRC (HCT116 and SW480) cells were subjected to the siRNA silencing and recombinant plasmid overexpression of NEIL1. Transfection of siNEIL1 significantly inhibited the cell growth. It also increased the Bax expression levels, while it decreased the Bcl-2 expression levels in human CRC cells, leading the Bax/Bcl-2 balance toward apoptosis. Moreover, the apoptosis was promoted through the caspase-9 signaling pathway. One the other hand, high expression of NEIL1 promoted the cell viability and reduced the apoptosis, inducing the balance of Bax/Bcl-2 in the human colon cancer cells to be antiapoptotic. In addition, the caspase-9 signaling pathway inhibited apoptosis, contrary to the results obtained by downregulating NEIL1 expression. Furthermore, NEIL1 was negatively regulated by miR-7-5p, indicating that miR-7-5p inhibited the NEIL1 expression after transcription. Overexpression of miR-7-5p reversed the effects of NEIL1 on these CRC cells. In conclusion, NEIL1 promotes the proliferation of CRC cells, which is regulated negatively by miR-7-5p. These findings suggest that NEIL1 is a potential therapeutic target for CRC.

• DNMT inhibitors
• colorectal cancer
• methylation
• therapy

• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy
• DNA Methylation/genetics
• Humans

• Apoptosis
• Glioma
• TTDA
• p53

Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

• DNA repair
• base excision repair (BER)glycosylases
• colorectal cancer
• oxidative DNA damage

• DNA repair
• base excision repair
• epigenetic demethylation
• genotoxicity assays
• knockout cell lines
• mutagenesis.

• Wnt-based therapeutics
• Wnts
• canonical Wnt signaling pathway
• colorectal cancer
• non-canonical Wnt signaling pathway

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Liver metastasis is the major cause of CRC patient mortality, occurring in 60% patients with no effective therapies. Although studies have indicated the role of miRNAs in CRC, an in-depth miRNA expression analysis is essential to identify clinically relevant miRNAs and understand their potential in targeting liver metastasis. Here we analyzed miRNA expressions in 405 patient tumors from publicly available colorectal cancer genome sequencing project database. Our analyses showed miR-132, miR-378f, miR-605 and miR-1976 to be the most significantly downregulated miRNAs in primary and CRC liver metastatic tissues, and CRC cell lines. Observations in CRC cell lines indicated that ectopic expressions of miR-378f, -605 and -1976 suppress CRC cell proliferation, anchorage independent growth, metastatic potential, and enhance apoptosis. Consistently, CRC patients with higher miR-378f and miR-1976 levels exhibited better survival. Together, our data suggests an anti-tumorigenic role of these miRNAs in CRC and warrant future in vivo evaluation of the molecules for developing biomarkers or novel therapeutic strategies.

• GPC6
• NPC
• genomic variations
• invasion
• migration
• proliferation

Research on DNA methylation offers great potential for the identification of biomarkers that can be applied for accurately assessing an individual's risk for cancer. In this article, we try to find the ideal epigenetic genes involved in colorectal cancer (CRC) based on a CRC database and our CRC cohort. The top 20 genes with an extremely high frequency of hypermethylation in CRC were identified in the latest database. Remarkably, 3 HOXA genes were included in this list and ranked at the top. The percentage of methylation in the HOXA5, HOXA2, and HOXA6 genes in CRC were up to 67.62, 58.36, and 31.32%, respectively, and ranked first in CRC among all human tumor tissues. Paired colorectal tumor samples and adjacent non-tumor colorectal tissue samples and four CRC cell lines were selected for MethylTarget™ assays. The results demonstrated that CRC tissues and cells had a stronger methylation status around the 3 HOXA gene promoter regions compared with adjacent non-tumor colonic tissue samples. The Receiver operator characteristic curve (ROC) curves for HOXA genes show excellent diagnostic ability in distinguishing tissue from healthy individuals and CRC patients, especially for Stage I patients (AUC = 0.9979 in HOXA2, 0.9309 in HOXA5, and 0.8025 in HOXA6). An association analysis between the methylation pattern of HOXA genes and clinical indicators was performed and found that HOXA2 methylation was significantly associated with age, N, stage, M, lymphovascular invasion, perineural invasion, lymph node number. HOXA5 methylation was associated with age, T, M, stage, and tumor status, and HOXA6 methylation was associated with age and KRAS mutation. Notably, we found that the highest methylation of HOXA5 and HOXA2 occurs in the early stages of colorectal cancer tissues such as stage I, N0, MO, and non-invasive tissues. The methylation levels declined as tumors progressed. However, methylation level at any stage of the tumor was still significantly higher than in normal tissues (p < 0.0001). The mRNA of the 3 HOXA genes was downregulated in early tumor stages due to hypermethylation of CpG islands adjacent to the promoters of the genes. In addition, hypermethylation of HOXA5 and HOXA6 mainly occurred in patients < 60 years old and with MSI-L, MSS, CIMP.L and non-CIMP tumors. Together, this suggests that epigenetic silencing of 3 adjacent HOXA genes may be an important event in the progression of colorectal cancer.

• HOXA2
• HOXA5
• HOXA6
• biomarker
• colorectal cancer
• early stage
• methylation

Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies. We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity.

Genomic methylation in whole blood from 27 twin pairs discordant for SSc was assayed over 450 K CpG sites. In silico integration with reported differentially methylated cytosines, differentially expressed genes, and regulatory annotation was conducted to validate and interpret the results.

A total of 153 unique cytosines in limited cutaneous SSc (lcSSc) and 266 distinct sites in diffuse cutaneous SSc (dcSSc) showed suggestive differential methylation levels in affected twins. Integration with available data revealed 76 CpGs that were also differentially methylated in blood cells from lupus patients, suggesting their role as potential epigenetic blood biomarkers of autoimmunity. It also revealed 27 genes with concomitant differential expression in blood from SSc patients, including IFI44L and RSAD2. Regulatory annotation revealed that dcSSc-associated CpGs (but not lcSSc) are enriched at Encyclopedia of DNA Elements-, Roadmap-, and BLUEPRINT-derived regulatory regions, supporting their potential role in disease presentation. Notably, the predominant enrichment of regulatory regions in monocytes and macrophages is consistent with the role of these cells in fibrosis, suggesting that the observed cellular dysregulation might be, at least partly, due to altered epigenetic mechanisms of these cells in dcSSc.

These data implicate epigenetic changes in the pathogenesis of SSc and suggest functional mechanisms in SSc etiology.

The online version of this article (10.1186/s13148-019-0652-y) contains supplementary material, which is available to authorized users.

• Blood
• DNA methylation
• Genome
• Systemic sclerosis
• Twins

DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes.

Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed.

According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations.

DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.

The online version of this article (10.1186/s12885-018-4609-x) contains supplementary material, which is available to authorized users.

• Adenoma
• Colorectal cancer
• DNA methylation
• Methyl capture sequencing
• Mutation
• TP53 signaling pathway

GATA4 is a zinc finger DNA-binding protein that plays an important role in mammalian liver development. However, the effects of GATA4 in hepatoblastoma (HB), a common liver cancer in pediatric patients, remain largely unknown. In this study, we demonstrate that GATA4 promotes growth and survival in the Huh6 human hepatoblastoma cell line. GATA4 expression was high in Huh6 cells, and its knockdown decreased expression of Dickkopf-related protein 3 (DKK3), a gene that may contribute to premature or undifferentiated phenotypes in HB. GATA4 also directly bound to the promoter regions of the miRNA miR125b and inhibited its expression in Huh6 cells. DKK3 was a direct target of miR125b in Huh6 cells. Inhibition of miR125b or overexpression of DKK3 promoted proliferation, survival, migration, and invasion in Huh6 cells. This is the first report to demonstrate that GATA4 promotes oncogenesis by inhibiting miR125b-dependent suppression of DKK3 expression. This GATA4/miR125b/DKK3 axis may be a major regulator of growth, migration, invasion, and survival in hepatoma cells, and is therefore a potential therapeutic target or biomarker for progression in HB patients.

• DKK3
• GATA4
• hepatoblastoma
• miR125b

The ‘junk DNA’ that has haunted human genetics for a long time now turns out to hold enormous hidden treasures. As species had their genomes and transcriptomes sequenced, there are an overwhelming number of lncRNA transcripts being reported, however, less than 100 of them have been functionally characterized. DNA damage is recognized and quickly repaired by the cell, with increased expression of numerous genes involved in DNA repair. Most of the time the studies have focused only on proteins involved in these signaling pathways. However, recent studies have implied that lncRNAs can be broadly induced by DNA damage and regulate DNA repair processes by various mechanisms. In this paper, we focus on recent advances in the identification and functional characterization of novel lncRNAs participating in DNA double strand break repair.

• DNA double strand break
• DNA repair
• cancer
• chemoresistance
• lncRNA

Transducin-like enhancer of Split3 (TLE3) serves as a transcriptional corepressor during cell differentiation and shows multiple roles in different kinds of cancers. Recently, TLE3 together with many other genes involved in Wnt/β-catenin pathway were detected hyper-methylated in colorectal cancer (CRC). However, the potential role and the underlying mechanism of TLE3 in CRC progression remain scarce.

Gene expression profiles were analyzed in The Cancer Genome Atlas (TCGA) microarray dataset of 41 normal colorectal intestine tissues and 465 CRC tissues. Western blot and Real-time Quantitative PCR (RT-qPCR) were respectively performed to detect protein and mRNA expression in 8 pairs of CRC tissue and matched adjacent normal mucosa. Immunohistochemistry (IHC) was conducted to evaluate TLE3 protein expression in 105 paraffin-embedded, archived human CRC tissues from patients, whose survival data were analyzed with Kaplan-Meier method. In vitro experiments including MTT assay, colony formation assay, and soft agar formation assay were used to investigate the effects of TLE3 on CRC cell growth and proliferation. Additionally, subcutaneous tumorigenesis assay was performed in nude mice to confirm the effects of TLE3 in vivo. Furthermore, gene set enrichment analysis (GSEA) was run to explore potential mechanism of TLE3 in CRC, and then we measured the distribution of CRC cell cycle phases and apoptosis by flow cytometry, as well as the impacts of TLE3 on MAPK and AKT signaling pathways by Western blot and RT-qPCR.

TLE3 was significantly down-regulated in 465 CRC tissues compared with 41 normal tissues. Both protein and mRNA expressions of TLE3 were down-regulated in CRC compared with matched adjacent normal mucosa. Lower expression of TLE3 was significantly associated with poorer survival of patients with CRC. Besides, knock down of TLE3 promoted CRC cell growth and proliferation, while overexpression of TLE3 showed suppressive effects. Furthermore, overexpression of TLE3 caused G1-S phase transition arrest, inhibition of MAPK and AKT pathways, and up-regulation of p21Cip1/WAF1 and p27Kip1.

This study indicated that TLE3 repressed CRC proliferation partly through inhibition of MAPK and AKT signaling pathways, suggesting the possibility of TLE3 as a biomarker for CRC prognosis.

The online version of this article (doi:10.1186/s13046-016-0426-8) contains supplementary material, which is available to authorized users.

• Colorectal cancer
• Prognosis
• Proliferation
• TLE3
• p21Cip1/WAF1
• p27Kip1

• APC
• Adenoma
• WNT signaling pathway
• colorectal cancer
• gene expression
• promoter and gene body methylation
• whole methylome analysis
• β-catenin mutation

The effects of abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 on human cancer have not been fully elucidated. In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database. A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer. As a mechanism underlying the reduced expression of NEIL1 in cancer, the epigenetic silencing of NEIL1 through promoter hypermethylation was found. Finally, we investigated the reason why an elevated NEIL3 expression level was associated with an increased number of somatic mutations in cancer and found that NEIL3 expression was positively correlated with the expression of APOBEC3B, a potent inducer of mutations, in diverse cancers. These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.

• DNA glycosylase
• HPRT assay
• NEIL1
• Nuclear localization signal (NLS)
• TCGA
• p.Q282Stop-type NEIL1

Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

• Epigenetic
• DNA damage
• DNA repair
• DNA repair deficiency disorders
• Epimutation
• Genomic instability
• Germ-line mutation
• MicroRNAs
• Precancerous conditions
• Gastrointestinal cancer