• T cell
• dog
• gastrointestinal
• inflammatory bowel disease
• lymphoma
• microRNA

• DNA methylation
• cancer
• miRNA

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• DNA Methylation/genetics
• Neoplasms/genetics
• Epigenesis, Genetic/genetics
• Gene Silencing

• K12 GM093857 NIGMS NIH HHS
• KL2 TR002648 NCATS NIH HHS
• P20 CA252717 NCI NIH HHS
• P30 CA016059 NCI NIH HHS

• DNA methylation and biomarkers
• MIRN138 microRNA
• colorectal neoplasms
• human

Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy.

• DNA methylation
• biomarkers
• cancer
• clinical applications
• epigenetics
• microRNAs

• Biomarkers, Tumor
• Breast Neoplasms/genetics
• DNA Methylation
• DNA, Neoplasm/genetics
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Therapy
• Histone Code
• Humans
• Lung Neoplasms/genetics
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/therapy
• Ovarian Neoplasms/genetics
• Prognosis
• RNA Processing, Post-Transcriptional
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics
• Stomach Neoplasms/genetics
• Translational Research, Biomedical

• Gestational diabetes mellitus
• MiR-34b-3p
• Migration
• PDK1
• Viability

• CTCs
• biomarkers
• circulating nucleic acids
• colorectal cancer
• epigenetics
• extracellular vesicles
• liquid biopsy
• precision oncology

DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC.

We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage.

Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only.

Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.

• CRC stage
• Colorectal adenoma
• Colorectal cancer
• DNA methylation
• Odds ratio
• Risk stratification
• Screening biomarker
• Stage-specific
• Stool

• Colorectal cancer
• miRNAs
• target therapy

• cancer stem cells
• colorectal cancer
• miRNAs
• regulatory mechanisms

Lung cancer is the most common incident cancer, with a high mortality worldwide, and non‐small‐cell lung cancer (NSCLC) accounts for approximately 85% of cases. Numerous studies have shown that the aberrant expression of microRNAs (miRNAs) is associated with the development and progression of cancers. However, the clinical significance and biological roles of most miRNAs in NSCLC remain elusive. In this study, we identified a novel miRNA, miR‐34b‐3p, that suppressed NSCLC cell growth and investigated the underlying mechanism. miR‐34b‐3p was down‐regulated in both NSCLC tumour tissues and lung cancer cell lines (H1299 and A549). The overexpression of miR‐34b‐3p suppressed lung cancer cell (H1299 and A549) growth, including proliferation inhibition, cell cycle arrest and increased apoptosis. Furthermore, luciferase reporter assays confirmed that miR‐34b‐3p could bind to the cyclin‐dependent kinase 4 (CDK4) mRNA 3′‐untranslated region (3′‐UTR) to suppress the expression of CDK4 in NSCLC cells. H1299 and A549 cell proliferation inhibition is mediated by cell cycle arrest and apoptosis with CDK4 interference. Moreover, CDK4 overexpression effectively reversed miR‐34‐3p‐repressed NSCLC cell growth. In conclusion, our findings reveal that miR‐34b‐3p might function as a tumour suppressor in NSCLC by targeting CDK4 and that miR‐34b‐3p may, therefore, serve as a biomarker for the diagnosis and treatment of NSCLC.

• CDK4
• NSCLC
• apoptosis
• cell cycle
• cell proliferation
• miR-34b-3p
• miRNA high throughput

As the second-most-common cause of cancer death, colorectal cancer (CRC) has been recognized as one of the biggest health concerns in advanced countries. The 5-year survival rate for patients with early-stage CRC is significantly better than that for patients with CRC detected at a late stage. The primary target for CRC screening and prevention is advanced neoplasia, which includes both CRC itself, as well as benign but histologically advanced adenomas that are at increased risk for progression to malignancy. Prevention of CRC through detection of advanced adenomas is important. It is, therefore, necessary to develop more efficient detection methods to enable earlier detection and therefore better prognosis. Although a number of CRC diagnostic methods are currently used for early detection, including stool-based tests, traditional colonoscopy, etc., they have not shown optimal results due to several limitations. Hence, development of more reliable screening methods is required in order to detect the disease at an early stage. New screening tools also need to be able to accurately diagnose CRC and advanced adenoma, help guide treatment, and predict the prognosis along with being relatively simple and non-invasive. As part of such efforts, many proposals for the early detection of colorectal neoplasms have been introduced. For example, metabolomics, referring to the scientific study of the metabolism of living organisms, has been shown to be a possible approach for discovering CRC-related biomarkers. In addition, a growing number of high-performance screening methodologies could facilitate biomarker identification. In the present, evidence-based review, the authors summarize the current state as recognized by the recent guideline recommendation from the American Cancer Society, US Preventive Services Task Force and the United States Multi-Society Task Force and discuss future direction of screening tools for colorectal cancer. Further, we highlight the most interesting publications on new screening tools, like molecular biomarkers and metabolomics, and discuss these in detail.

• Colorectal cancer
• Screening tool
• Early detection
• Biomarkers
• Metabolomics

• Colorectal cancer
• miR-34
• miRNA delivery
• p53

• Colorectal cancer
• LncRNAs
• TUSC7
• miR-10a

• Colorectal cancer
• Long non-coding RNAs
• MicroRNAs
• Prognosis
• Therapeutic response

Two molecular pathways promote the development of colorectal cancer (CRC). One is termed “microsatellite stable” (MSS) whereas the other is characterized by “microsatellite instability” (MSI or MIN). In addition, the CpG island methylation phenotype is known to be an important alteration as a third molecular type. Thus, DNA methylation is thought to provide potential biomarkers for assessment of cancer risk in normal mucosa. In addition, it is also known that colonic location is an important parameter in the development of CRC.

We examined the surrounding normal mucosa in three parts of the colon. Next, we quantified DNA methylation levels of SFRP1, SFRP2, SFRP5, DKK2, DKK3, mir34b/c, RASSF1A, IGFBP7, CDKN2A, and MLH1 in isolated cancerous glands and crypts of normal colorectal mucosa adjacent to CRCs using a pyrosequencer.

DNA methylation levels of SFRP1, SFRP2, DKK2, and mir34b/c were significantly higher in CRCs with an MSS phenotype than in those with an MSI phenotype. The average level of methylation in normal crypts did not decrease with the distance from the tumor, irrespective of microsatellite status or the tumor location. DNA methylation levels in SFRP1 and SFRP2 genes in normal crypts were significantly higher in left-side than right-side CRC with an MSS phenotype. Finally, the genes were classified into three types based on the methylation frequencies in normal crypts, including type I (SFRP1 and SFRP2I), type II (DKK2 and mir34b/c), and type III (others).

Our results showed that DNA methylation of SFRP1 and SFRP2 might be useful to predict cancer risk of surrounding normal mucosa. In addition, a field effect may be present in CRC, affecting both adjacent and non-adjacent normal mucosa.

The online version of this article (doi:10.1186/s13148-017-0352-4) contains supplementary material, which is available to authorized users.

• Colorectal cancer
• Crypt isolation
• DNA methylation
• Microsatellite instability
• Normal mucosa

• Colorectal cancer
• Diagnostic biomarkers
• Methylation biomarkers
• Prognostic biomarkers and therapeutic biomarkers

• Adenomatous Polyposis Coli Protein/genetics
• Adenomatous Polyposis Coli Protein/metabolism
• Biomarkers, Tumor/blood
• Colorectal Neoplasms/blood
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• DNA Methylation
• Early Detection of Cancer
• Epigenomics
• Feces/chemistry
• Humans
• Microsatellite Instability
• Prognosis
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Treatment Outcome

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Cell Cycle Checkpoints
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Humans
• MicroRNAs/metabolism
• Models, Theoretical
• Polymorphism, Single Nucleotide
• Practice Guidelines as Topic
• RNA, Messenger/metabolism

MicroRNAs (miRNAs) are highly conserved noncoding RNAs of about 19-25 nucleotides. Through specifically pairing with complementary sites in 3' untranslated regions (UTRs) of target mRNAs, they mediate post-transcriptional silencing. MicroRNAs have been implicated in many physiological processes including proliferation, differentiation, development, apoptosis, and metabolism. In recent years many studies have revealed that the aberrant expression of miRNA is closely related to oncogenesis and is now an intense field of study. Mir-148a is aberrantly expressed in various cancers and has been identified as an oncogenic or tumor suppressor with crucial roles in the molecular mechanisms of oncogenesis. In this review, we have summarized the role of mir-148a in the oncogenic pathways of gastric, liver, breast and urogenital cancers, and in neurogliocytoma oncogenesis. Studying the functional role of mir-148a is crucial in discovering novel tumor molecular markers and identifying potential therapeutic targets.

• biological function.
• cancer
• miRNA
• mir-148a
• oncogene
• tumor suppressor gene

• biomarker
• colorectal neoplasm
• metastasis
• miRNA
• target gene

• Animals
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics

• Colorectal cancer
• Copy number variations
• Data integration
• Gene expression
• Methylome
• miRNA expression

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Computational Biology
• DNA Copy Number Variations
• DNA Methylation
• Databases, Genetic
• Epigenesis, Genetic
• Gene Dosage
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Genomics/methods
• High-Throughput Nucleotide Sequencing
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Phenotype
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Signal Transduction
• Systems Integration

• colorectal cancer
• early markers
• let-7
• miRNA
• plasma DNA
• stool DNA

• Colorectal cancer
• DNA methylation
• Epigenetic regulation
• MicroRNA

• BRAF
• KRAS
• colorectal carcinoma

• Circulating biomarker
• MicroRNA
• Pediatric cancer

• Adolescent
• Biomarkers, Tumor/metabolism
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• MicroRNAs/metabolism
• Neoplasms/diagnosis
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• RNA, Neoplasm/metabolism

MicroRNAs (miRNAs) are a class of small non-protein-coding RNAs, which are often aberrantly expressed in the progression of various malignant tumors. Digestive system cancers are major causes of death all over the world. The finding of miRNAs provides a new direction for the diagnosis and therapy of digestive system cancers. Recent studies have demonstrated that miR-148a is aberrantly down-regulated in various digestive system cancers, including gastric cancer, hepatocellular cancer, pancreatic cancer and colorectal cancer. MiR-148a play a crucial role in the progression of these tumors as a tumor suppressor gene. This article will review the progress in research of miR-148a in digestive system cancers.

• miR-148a
• Digestive system cancers

• CFNA
• DNA methylation
• DNA mutation
• biomarkers
• cell-free nucleic acids
• colorectal cancer
• miRNAs
• noninvasive tests

The molecular genetics of gastric carcinoma (GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori (H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability (MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene (CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, may provide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mTOR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.

• Molecular genetics
• Lauren classification
• Intestinal type gastric cancer
• Diffuse type gastric cancer
• Molecular Biomarker

• Cancer
• Colon
• Cribado
• Cáncer
• Diagnosis
• Diagnóstico
• Micro-RNA
• Screening

There is an increasing research interest regarding deregulation of microRNA (miRNA) expression by DNA methylation in cancer. The aim of this study was to integrate data from publications and identify miRNA genes shown to be silenced in the highest number of cancer types and thus facilitate biomarker and therapeutic development. We integrated relevant data from 104 published scientific articles. The following databases and bioinformatics tools were used for the analysis: miRBase, miRNA Genomic Viewer, MultAlin, miRNA SNiPer, TargetScan, Ensembl, MethPrimer, TarBase, miRecords, and ChIPBase. Among 2578 currently known human miRNAs and 158 known to be regulated by DNA methylation, miR-34 gene family (miR-34a, -34b, and -34c) was shown to be silenced by DNA methylation in the highest number of cancer types. Consequently, we developed the miR-34 gene family regulatory atlas, consisting of its upstream regulators and downstream targets including transcription factor binding sites (TFBSs), CpG islands, genetic variability and overlapping QTL. MicroRNA-34 gene family has a potential as a cancer biomarker and target for epigenetic drugs. This potential has already been recognized as MRX34 is well into phase I studies. The developed miR-34 gene family regulatory atlas presented in this study provides a starting point for further analyses and could thus facilitate development of therapeutics.

• DNA methylation
• Kunej
• Slovenia
• Tanja
• University of Ljubljana
• cancer
• miR-34
• miRNA
• microRNA

• 5-aza-2'-deoxycytidine
• DNA methylation
• MIR1247
• MIR941
• epigenetics
• gastric cancer
• microRNA

• cancer
• metastasis
• miR-34
• miR-34a
• miR-34b/c
• p53
• tumor suppression

MicroRNAs are evolutionarily conserved small non-coding RNA molecules encoded by eukaryotic genomic DNA, and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs, resulting in translational repression or degradation of target mRNAs. They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities. Altered expression of microRNAs has been found in various human diseases including cancer. Many efforts have been made to discover the characteristic microRNA expression profiles, to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers. With the application of DNA microarray, real-time quantitative polymerase chain reaction and other molecular biology techniques, increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells, but also extracellularly in plasma of patients, postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets. This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers, colorectal cancer, especially the identification of those specifically altered microRNAs in colorectal cancer, validation for their relevance to clinical pathological parameters of patients, functional analyses and potential applications of these microRNAs.

• MicroRNA
• Epigenetic modification
• Colorectal cancer
• Marker
• Therapy

• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Epigenesis, Genetic
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/metabolism
• Molecular Biology
• Neoplasms/genetics
• Neoplasms/metabolism
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Real-Time Polymerase Chain Reaction
• Treatment Outcome

Cancer is a complex disease caused by genetic and epigenetic abnormalities that affect gene expression. The progression from precursor lesions to invasive cervical cancer is influenced by persistent human papilloma virus (HPV) infection, which induces changes in the host genome and epigenome. Epigenetic alterations, such as aberrant miRNA expression and changes in DNA methylation status, favor the expression of oncogenes and the silencing of tumor-suppressor genes. Given that some miRNA genes can be regulated through epigenetic mechanisms, it has been proposed that alterations in the methylation status of miRNA promoters could be the driving mechanism behind their aberrant expression in cervical cancer. For these reasons, we assessed the relationship among HPV infection, cellular DNA methylation and miRNA expression. We conclude that alterations in the methylation status of protein-coding genes and various miRNA genes are influenced by HPV infection, the viral genotype, the physical state of the viral DNA, and viral oncogenic risk. Furthermore, HPV induces deregulation of miRNA expression, particularly at loci near fragile sites. This deregulation occurs through the E6 and E7 proteins, which target miRNA transcription factors such as p53.

• Hepatocellular carcinoma
• Methylation
• miR-34a
• miR-34b/c