• Sfrp1
• biomarker
• epigenetics
• liquid biopsy
• methylation
• pancreatic ductal adenocarcinoma

• DNA
• RNA
• biomarkers
• blood
• pancreatic ductal adenocarcinoma
• protein

• JAM3
• PAX1
• DNA methylation
• High-grade squamous intraepithelial lesions
• Hr-HPV

• Humans
• Female
• DNA Methylation
• Papillomavirus Infections/diagnosis
• Papillomavirus Infections/genetics
• Papillomavirus Infections/virology
• Adult
• Middle Aged
• Uterine Cervical Neoplasms/diagnosis
• Uterine Cervical Neoplasms/genetics
• Uterine Cervical Neoplasms/virology
• Uterine Cervical Neoplasms/pathology
• Paired Box Transcription Factors/genetics
• Cell Adhesion Molecules/genetics
• Cell Adhesion Molecules/metabolism
• Squamous Intraepithelial Lesions/genetics
• Squamous Intraepithelial Lesions/virology
• Squamous Intraepithelial Lesions/pathology
• Squamous Intraepithelial Lesions/diagnosis
• Biomarkers, Tumor/genetics
• Uterine Cervical Dysplasia/diagnosis
• Uterine Cervical Dysplasia/genetics
• Uterine Cervical Dysplasia/virology
• Uterine Cervical Dysplasia/pathology
• Human papillomavirus 16/genetics
• Human papillomavirus 16/isolation & purification
• Squamous Intraepithelial Lesions of the Cervix/virology
• Squamous Intraepithelial Lesions of the Cervix/genetics
• Squamous Intraepithelial Lesions of the Cervix/diagnosis
• Squamous Intraepithelial Lesions of the Cervix/pathology
• Risk Factors

• DNA methylation
• biomarker
• cell-free DNA
• pancreatic ductal carcinoma
• peptide nucleic acid

• Body fluid identification
• CpG sites
• MSRE PCR

• Humans
• Male
• Female
• DNA Methylation
• Body Fluids
• Saliva
• Multiplex Polymerase Chain Reaction
• Semen
• DNA
• DNA Restriction Enzymes/metabolism
• Genetic Markers
• Chromosomes, Human, Y
• Forensic Genetics

• Charité - Universitätsmedizin Berlin (3093)

• DNA methylation
• cervical lesions
• conditional inference tree
• junctional adhesion molecule 3
• paired box gene 1

• Female
• Humans
• Atypical Squamous Cells of the Cervix
• Cell Adhesion Molecules
• DNA Methylation
• Early Detection of Cancer
• Human Papillomavirus Viruses
• Junctional Adhesion Molecule C
• Retrospective Studies
• Uterine Cervical Neoplasms/diagnosis

• 2020SK53604 the Hunan Provincial Clinical Medical Technology Innovation Guiding Project, China

• Methylation driven pathways
• PanCa enriched methylated pathway
• Pancreatic cancer methylation markers
• Pre-cancer methylated pathways
• Signaling pathway targeted therapy

• Cell free biomarkers
• Liquid biopsy-based diagnostics
• Non-invasive biomarkers
• Pancreatic cancer biomarkers
• Proteomic biomarkers

• Humans
• Biomarkers, Tumor
• Early Detection of Cancer
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/pathology
• Liquid Biopsy/methods

• DNA methylation
• cell-free DNA
• circulating tumor DNA
• liquid biopsy
• liver metastases
• malignant liver tumors
• primary malignant liver tumors
• tissue of origin determination

• Biosensor
• Electrochemical impedance spectroscopy
• miR30e

• Humans
• DNA, Single-Stranded
• Cysteine
• Biosensing Techniques
• MicroRNAs
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Gold Colloid

• Circulating tumour DNA methylation
• Early detection
• Methylation haplotype blocks
• PDAC

• bioinformatics
• biomarkers
• epigenetic
• microRNA
• preeclampsia
• therapeutic targets

• Pregnancy
• Female
• Humans
• Pre-Eclampsia/genetics
• Pre-Eclampsia/metabolism
• MicroRNAs/metabolism
• Computational Biology
• Placenta/metabolism
• Biomarkers/metabolism

• Artificial intelligence
• Early diagnosis
• Liquid biopsy
• Pancreatic cancer
• Pancreatic cancer biomarkers
• Pancreatic cancer screening
• Pancreatic ductal adenocarcinoma

• Artificial Intelligence
• Biomarkers, Tumor
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/therapy
• Early Detection of Cancer
• Humans
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/therapy

We aimed to explore the role of Solute Carrier Family 35 Member F2 (SLC35F2) in pancreatic cancer (PCa) and to further study whether SLC35F2 regulates cisplatin resistance of PCa cells through the modulation of RNA binding motif protein 14 (RBM14) expression. SLC35F2 expression in 60 pairs of PCa tissues and adjacent ones was studied by RT-PCR analysis. Meanwhile, SLC35F2 expression levels in PCa cell lines were also evaluated by qPCR assay. In addition, SLC35F2 knockdown models were constructed in PCa cisplatin-resistant cells. Furthermore, we determined the interaction between SLC35F2 and RBM14 via luciferase assay. The findings of the present study demonstrated that SLC35F2 was significantly upregulated in PCa tissues. High level of SLC35F2 indicated higher incidence of metastasis and shorter survival rates. In vitro cell experiments revealed that knockdown of SLC35F2 suppressed cell invasion and metastasis capacity of cisplatin-resistant PCa cell lines PANC-1/DDP and CFPAC-1/DDP. It was also suggested that the key protein RBM14 in the SLC35F2 knockdown group was remarkably reduced. SLC35F2 can bind to RBM14 specifically. Overexpression of RBM14 partially reversed the effects of knockdown of SLC35F2 on the development of PCa. SLC35F2 expression in PCa tissues and cell lines is remarkably increased. In addition, it was also suggested that SLC35F2 may regulate cisplatin resistance of PCa cells through modulating RBM14 expression. In conclusion, it is conceivable from the study that SLC35F2 was remarkably upregulated in PCa and promoted the malignancy of PCa via regulating RBM14.

Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation.

Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS).

A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037).

Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.

• KRAS
• TP53
• circulating tumor DNA
• ctDNA
• pancreatic cancer

Epigenetic alterations cause changes in gene expression without affecting the DNA sequence and are found to affect several molecular pathways in pancreatic tumors. Such changes are reversible, making them potential drug targets. Furthermore, epigenetic alterations occur early in the disease course and may thus be explored for early detection. Hence, a deeper understanding of epigenetics in pancreatic cancer may lead to improved diagnostics, treatments, and prognostication.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC.

The melanoma antigen gene family A (MAGEA) family of proteins comprises of cancer-testis antigens that are highly expressed in a number of tumours but are minimally expressed in normal cells. Due to its expression characteristics, this protein family has become a popular target for anti-cancer drugs and immunotherapy research over recent years. Although, elevated expression levels of MAGEA6 has been found in different types of tumours, there remains to be insufficient information on the function of MAGEA6 and its associated gene regulation pathways. The present study used Transwell, Cell Counting Kit-8 and wound healing assays to analyse the effects of MAGEA6 on Eca109 cell invasion, migration and proliferation. The main functions and pathways involved in MAGEA6 were predicted by Illumina Hiseq screening for mutually regulated genes and core genes. Eca109 cell line with a high expression of MAGEA6 was a stable cell line obtained by transfection in the early stage, and this cell line was used in subsequent experiments. Transcriptome sequencing was performed on this cell line and the Eca109 cell line that normally expressed MAGEA6. It was revealed that a high expression of MAGEA6 conferred a significant stimulating effect on cell proliferation whilst also significantly increasing cell invasion and migration. Transcriptomic analysis identified 14 differentially expressed genes and 13 core regulatory genes closely associated with MAGEA6 expression regulation, such as methylsterol monooxygenase 1 (MSMO1). The present study suggest that MAGEA6 positively regulated MSMO1 expression, which may serve an oncogenic role in cells through this regulatory effect. Overall, this provided a novel route of investigation for an in-depth study of the regulatory function of MAGEA6.

Pancreatic ductal adenocarcinoma is a leading cause of cancer death worldwide. Due to the frequently late diagnosis, early metastasis and high therapy resistance curation is rare and prognosis remains poor overall. To provide early diagnostic and therapeutic predictors, various molecules from blood, tissue and other origin e.g., saliva, urine and stool, have been identified as biomarkers. This review summarizes current trends in biomarkers for diagnosis and therapy of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.

• biomarker
• molecular diagnostics
• pancreatic ductal adenocarcinoma
• targeted therapy

Pancreatic cancer is a highly lethal malignancy. Dysregulation of epigenetic mechanisms leads to abnormal patterns of gene expression contributing to the development and progression of cancer. We explored the ability of DNA methylation of PI3K-related genes to differentiate between malignant and healthy pancreatic tissue using distinct pancreatic cancer cohorts, and found that the methylation levels of the ITGA4, SFN, ITGA2, and PIK3R1 genes are altered in tumour samples since the early stages of malignant transformation and could serve as new diagnostic tools. We also demonstrate that these alterations correlate with overall survival and recurrence-free survival of the patients suggesting that its assessment can serve as independent prognostic indicators of patients’ survival with higher sensitivity and specificity than the currently implemented biomarkers. Therefore, the methylation profile of genes involved in this pathway may be an alternative method for predicting cell malignancy and help doctors’ decisions on patient care.

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.

Genomic DNA methylation is involved in many diseases and is expected to be a specific biomarker for even the pre-symptomatic diagnosis of many diseases. Thus, a rapid and inexpensive detection method is required for disease diagnosis. We have previously reported that cytosine methylation in G-quadruplex (G4)-forming oligonucleotides develops different G4 topologies. In this study, we developed a method for detecting CpG methylation in G4-forming oligonucleotides based on the structural differences between methylated and unmethylated G4 DNAs. The differences in G4 topologies due to CpG methylation can be discriminated by G4 ligands. We performed a binding assay between methylated or unmethylated G4 DNAs and G4 ligands. The binding abilities of fluorescent G4 ligands to BCL-2, HRAS1, HRAS2, VEGF G4-forming sequences were examined by fluorescence-based microtiter plate assay. The differences in fluorescence intensities between methylated and unmethylated G4 DNAs were statistically significant. In addition to fluorescence detection, the binding of G4 ligand to DNA was detected by chemiluminescence. A significant difference was also detected in chemiluminescence intensity between methylated and unmethylated DNA. This is the first study on the detection of CpG methylation in G4 structures, focusing on structural changes using G4 ligands.

• DNA methylation
• G-quadruplex
• G4 ligand
• biosensor

• disseminated tumor cells
• liquid biopsy
• pancreatic ductal adenocarcinoma
• tumor staging

• Pancreatic cancer
• Pancreatic ductal adenocarcinoma
• Tumor microenvironment

• Carcinoma, Acinar Cell/genetics
• Carcinoma, Pancreatic Ductal/genetics
• Humans
• Neuroendocrine Tumors
• Pancreatic Neoplasms/genetics

• R01 CA199064 NCI NIH HHS
• T32 CA244125 NCI NIH HHS

• ARF
• Cdkn2a
• INK4a
• Pancreatic Progenitor Cells
• embryonic stem cells

• Animals
• Biomarkers/metabolism
• Cell Differentiation
• Cell Lineage/genetics
• Cyclin-Dependent Kinase Inhibitor p16/genetics
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Epigenesis, Genetic
• Gene Expression
• Genetic Loci
• Hepatocyte Nuclear Factor 3-beta/genetics
• Hepatocyte Nuclear Factor 3-beta/metabolism
• Hepatocyte Nuclear Factor 6/genetics
• Hepatocyte Nuclear Factor 6/metabolism
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Insulin-Secreting Cells/cytology
• Insulin-Secreting Cells/metabolism
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Mice
• Mouse Embryonic Stem Cells/cytology
• Mouse Embryonic Stem Cells/metabolism
• Nanog Homeobox Protein/genetics
• Nanog Homeobox Protein/metabolism
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Pancreas/cytology
• Pancreas/metabolism
• Primary Cell Culture
• Trans-Activators/genetics
• Trans-Activators/metabolism

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.

• DNA methylation
• epigenetics
• metastasis
• pancreatic cancer

Transforming growth factor (TGF) β signaling is intimately involved in nearly all aspects of tumor development and is known for its role as both a tumor suppressor in benign tissues and a tumor promoter in advanced cancers. This dual role is also reflected by cancer cell-produced TGFβ that eventually acts on the same cell(s) in an autocrine fashion. Recently, we observed that endogenous TGFB1 can inhibit rather than stimulate cell motility in cell lines with high autocrine TGFβ production. The unexpected anti-migratory role prompted us to evaluate how autocrine TGFβ1 impacts the cells’ migratory and proliferative responses to exogenous (recombinant human) TGFβ. Surprisingly, endogenous TGFB1 opposed the migratory and growth-inhibitory responses induced by exogenous TGFβ1 by driving a self-perpetuating feedforward loop involving MEK-ERK signaling. Our observation has implications for the use of TGFβ signaling inhibitors in cancer therapy.

Autocrine transforming growth factor β (aTGFβ) has been implicated in the regulation of cell invasion and growth of several malignant cancers such as pancreatic ductal adenocarcinoma (PDAC) or triple-negative breast cancer (TNBC). Recently, we observed that endogenous TGFB1 can inhibit rather than stimulate cell motility in cell lines with high aTGFβ production and mutant KRAS, i.e., Panc1 (PDAC) and MDA-MB-231 (TNBC). The unexpected anti-migratory role prompted us to evaluate if aTGFβ1 may be able to antagonize the action of exogenous (recombinant human) TGFβ (rhTGFβ), a well-known promoter of cell motility and growth arrest in these cells. Surprisingly, RNA interference-mediated knockdown of the endogenous TGFB1 sensitized genes involved in EMT and cell motility (i.e., SNAI1) to up-regulation by rhTGFβ1, which was associated with a more pronounced migratory response following rhTGFβ1 treatment. Ectopic expression of TGFB1 decreased both basal and rhTGFβ1-induced migratory activities in MDA-MB-231 cells but had the opposite effect in Panc1 cells. Moreover, silencing TGFB1 reduced basal proliferation and enhanced growth inhibition by rhTGFβ1 and induction of cyclin-dependent kinase inhibitor, p21^WAF1. Finally, we show that aTGFβ1 promotes MEK-ERK signaling and vice versa to form a self-perpetuating feedforward loop that is sensitive to SB431542, an inhibitor of the TGFβ type I receptor, ALK5. Together, these data suggest that in transformed cells an ALK5-MEK-ERK-aTGFβ1 pathway opposes the promigratory and growth-arresting function of rhTGFβ1. This observation has profound translational implications for TGFβ signaling in cancer.

• SNAIL
• WAF1
• autocrine regulation
• breast cancer
• cell growth
• extracellular-regulated kinase
• pancreatic cancer
• transforming growth factor β

• Amyotrophic lateral sclerosis
• Cell-free DNA
• DNA methylation
• Diagnostic tool
• Liquid biopsy
• Neurodegenerative diseases

• biomarkers
• pancreatic cancer
• pancreatic ductal adenocarcinoma
• predictive markers
• prognostic markers

Pancreatic adenocarcinoma (PAAD) is the most serious solid tumor type throughout the world. The present study aimed to identify novel biomarkers and potential efficacious small drugs in PAAD using integrated bioinformatics analyses. A total of 4777 differentially expressed genes (DEGs) were filtered, 2536 upregulated DEGs and 2241 downregulated DEGs. Weighted gene co-expression network analysis was then used and identified 12 modules, of which, blue module with the most significant enrichment result was selected. KEGG and GO enrichment analyses showed that all DEGs of blue module were enriched in EMT and PI3K/Akt pathway. Three hub genes (ITGB1, ITGB5, and OSMR) were determined as key genes with higher expression levels, significant prognostic value and excellent diagnostic efficiency for PAAD. Additionally, some small molecule drugs that possess the potential to treat PAAD were screened out, including thapsigargin (TG). Functional in vitro experiments revealed that TG repressed cell viability via inactivating the PI3K/Akt pathway in PAAD cells. Totally, our findings identified three key genes implicated in PAAD and screened out several potential small drugs to treat PAAD.

• biomarker
• connectivity map (CMap)
• pancreatic adenocarcinoma (PAAD)
• small molecule drug
• weighted co-expression network analysis (WGCNA)

• Barrett’s Esophagus
• Biomarkers
• Chromatin
• Colorectal Cancer
• DNA
• Diagnosis
• Esophageal Cancer
• Gastric Cancer
• Histone
• Methylation
• Noncoding RNA
• Pancreatic Cancer
• Predictive
• Prognosis
• Treatment

• biomarkers
• pancreatic cancer
• precision oncology
• targeted therapy

• Carcinoma, Pancreatic Ductal/genetics
• Genetic Predisposition to Disease/genetics
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Pancreatic Neoplasms/genetics
• Precision Medicine/methods
• Pancreatic Neoplasms

Clear cell renal cell carcinoma (ccRCC) accounts for 60-70% of renal cell carcinoma (RCC) cases. It is an urgent mission to find more therapeutic targets for advanced ccRCC. Leucine-rich a-2-glycoprotein 1 (LRG1) is a secreted protein associated with a variety of malignancies. Our study focused on the expression and mechanism of LRG1 in ccRCC based on data from The Cancer Genome Atlas (TCGA) and provided primary verification including LRG1 expression detection, LRG1 gene methylation detection, and downstream signaling detection. We found that LRG1 was overexpressed in ccRCC kidney tissue samples, and the methylation level of LRG1 gene was significantly decreased in ccRCC. Moreover, the expression of LRG1 was negatively related to patient survival. Based on our previous study and the verification reported in this article, we propose that demethylation-induced overexpression of LRG1 is likely to accelerate ccRCC progression via the TGF-β pathway.