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Early invasive growth and metastasis are features of pancreatic cancer that rely on its resistance to anoikis, an apoptosis program activated on loss of matrix anchorage. How anoikis is regulated is unclear. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE) was silenced, or p16 was overexpressed, in human pancreatic carcinoma cel...
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Context 1
... to these in silico analysis, GNE is up-regulated not only in pancreatic cancer but also in other human carcinomas, such as prostate cancer (Fig. 7). Results from another in silico analysis of normal pancreatic tissue in compar- ison to carcinoma showed ( Table 2) that there is a strong and significant (P0.05) down-regulation of GNE in normal tissue, according to data originally published by Iacobuzio-Donahue et al. (24). Interest- ingly, genes that were down-regulated in GNE-deficient p16-restored or GNE-siRNA-treated cells in comparison to wild-type Capan-1 carcinoma cells, such as GNE, PLAT, and VPS24, were also found to be down-regu- lated in normal pancreatic tissue. ...
Context 2
... ingly, genes that were down-regulated in GNE-deficient p16-restored or GNE-siRNA-treated cells in comparison to wild-type Capan-1 carcinoma cells, such as GNE, PLAT, and VPS24, were also found to be down-regu- lated in normal pancreatic tissue. In contrast, ASNS, CHAC1, PSAT1 and TRIB3, which are up-regulated in GNE-deficient Capan-1 cells, are also found to be up-regulated in normal pancreatic tissue in a significant way (Table 2). ...
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Citations
... Other DEPs induced by TPP-PA in P and PCSCs included DNAJB1 and HSPA6, which are chaperones implicated in ER stress and the unfolded protein response (UPR) [18,19], as well as in autophagy [20]. DNAJB1 and HSPA6 are two of the most significant genes that are dependent on ATF3, a transcription factor induced by TPP-PA in PCSCs (Table S1), which belongs to the pro-apoptotic ATF4/CHOP/ATF3 arm of the UPR [21]. ...
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... GNE is a bifunctional enzyme capable of initiating and regulating the biosynthesis of N-acetylneuraminic acid, which is essential for the de novo synthesis of sialic acid [66]. Sialic acid modification of the cell surface plays an important role in cell recognition, cell migration, signal transduction, embryonic development, maternal-fetal interactions, and body aging [66][67][68][69][70][71][72][73][74]. Homozygous knockouts of Gne or Cmas (downstream gene of GNE in the pathway of biosynthesis of N-acetylneuraminic acid) were lethal to embryos, with significantly decreased or completely eliminated sialic acid modifications on the trophectoderm cell surface [74]. ...
Background
Advanced maternal age (AMA) has increased in many high-income countries in recent decades. AMA is generally associated with a higher risk of various pregnancy complications, and the underlying molecular mechanisms are largely unknown. In the current study, we profiled the DNA methylome of 24 human chorionic villi samples (CVSs) from early pregnancies in AMA and young maternal age (YMA), 11 CVSs from early spontaneous abortion (SA) cases using reduced representation bisulfite sequencing (RRBS), and the transcriptome of 10 CVSs from AMA and YMA pregnancies with mRNA sequencing(mRNA-seq). Single-cell villous transcriptional atlas presented expression patterns of targeted AMA-/SA-related genes. Trophoblast cellular impairment was investigated through the knockdown of GNE expression in HTR8-S/Vneo cells.
Results
AMA-induced local DNA methylation changes, defined as AMA-related differentially methylated regions (DMRs), may be derived from the abnormal expression of genes involved in DNA demethylation, such as GADD45B. These DNA methylation changes were significantly enriched in the processes involved in NOTCH signaling and extracellular matrix organization and were reflected in the transcriptional alterations in the corresponding biological processes and specific genes. Furthermore, the DNA methylation level of special AMA-related DMRs not only significantly changed in AMA but also showed more excessive defects in CVS from spontaneous abortion (SA), including four AMA-related DMRs whose nearby genes overlapped with AMA-related differentially expressed genes (DEGs) (CDK11A, C19orf71, COL5A1, and GNE). The decreased DNA methylation level of DMR near GNE was positively correlated with the downregulated expression of GNE in AMA. Single-cell atlas further revealed comparatively high expression of GNE in the trophoblast lineage, and knockdown of GNE in HTR8-S/Vneo cells significantly impaired cellular proliferation and migration.
Conclusion
Our study provides valuable resources for investigating AMA-induced epigenetic abnormalities and provides new insights for explaining the increased risks of pregnancy complications in AMA pregnancies.
Graphical Abstract
... The balance between the ERK and AKT pathways may determine the fate of cells in terms of their survival or apoptosis. A previous study has suggested that apoptosis occurs via the ATF4-ATF3-CHOP pathway in GNE-knockout pancreatic cancer cells [117]. These studies show that various effector molecules targeting signal proteins in apoptotic pathways can aid in preventing cell apoptosis caused by Aβ accumulation and low SA, thereby preventing the progression of GNE myopathy (Fig. 1). ...
GNE myopathy is a hereditary muscle disorder characterized by muscle atrophy and weakness initially involving the lower distal extremities. The treatment of GNE myopathy mainly focuses on a sialic acid deficiency caused by a mutation in the GNE gene, but it has not achieved the expected effect. The main pathological features of GNE myopathy are myofiber atrophy and rimmed vacuoles, including accumulation of amyloid β, which is mainly found in atrophic muscle fibers. Although the role of amyloid β and other misfolded proteins on the nervous system has been widely recognized, the cause and process of the formation of amyloid β in the pathological process of GNE myopathy are unclear. In addition, amyloid β has been reported to be linked to quality control mechanisms of proteins, such as molecular chaperones, the ubiquitin–proteasome system, and the autophagy-lysosome system. Herein, we summarize the possible reasons for amyloid β deposition and illustrate amyloid β-mediated events in the cells and their role in muscle atrophy in GNE myopathy. This review represents an overview of amyloid β and GNE myopathy that could help identify a potential mechanism and thereby a plausible therapeutic for the disease.
... Patients were categorized into two groups (WT + LOSS and MUT + DEEP LOSS), as described in Table S1. A microarray data set (GSE22334 [14]) was obtained from the Gene Expression Omnibus (GEO) database [15]. In this data set, a CDKN2A-null CAPAN-1 pancreatic cell line was transfected with a CDKN2A-encoding plasmid to restore its function [14]). ...
... A microarray data set (GSE22334 [14]) was obtained from the Gene Expression Omnibus (GEO) database [15]. In this data set, a CDKN2A-null CAPAN-1 pancreatic cell line was transfected with a CDKN2A-encoding plasmid to restore its function [14]). The above gene expression data sets were subjected to gene set enrichment analysis (GSEA) against 50 cancer hallmarks [16] using the GSEA software (version 4.1.0, ...
... To identify the potential drugs being able to mimic CDKN2A activation, the differentially expressed genes (DEGs) from CDKN2-overexpressing CAPAN-1 cells (GSE22334 [14]) were prepared using the R-based web application, GEO2R [15]. These DEGs (Table S3) were queried using the Connectivity Map (CMap) database (accessed on 29 July 2020) [24]. ...
The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC). However, its prognostic and therapeutic roles in PDAC have not been extensively investigated yet. In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients’ prognosis and treatment. We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients. CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration. Chemosensitivity profiling of PDAC cell lines and patient-derived organoids found that CDKN2A inactivation was associated with the increased sensitivity to paclitaxel and SN-38 (the active metabolite of irinotecan). However, only paclitaxel can mimic the effect of CDKN2A restoration, and its drug sensitivity was correlated with genes related to estrogen response. Therefore, our study suggested that CDKN2A-inactivated PDAC patients could benefit from the precision treatment with paclitaxel, whose albumin-stabilized nanoparticle formulation (nab-paclitaxel) has been approved for treating PDAC.
... Bonferroni correction), which are both linked to migration of cells. The genes like GNE, TRIM , and PDE A greatly influenced cell junction [42][43][44]. Thus, dysregulated miRNAtarget gene pairs involved in these genes like miR-21/GNE, miR-369/TRIM , and miR-203a/PDE A might promote the migration of cancer cells. ...
Background:
Accumulating evidences demonstrated that microRNA-target gene pairs were closely related to tumorigenesis and development. However, the correlation between miRNA and target gene was insufficiently understood, especially its changes between tumor and normal tissues.
Objectives:
The aim of this study was to evaluate the changes of correlation of miRNAs-target pairs between normal and tumor.
Materials and methods:
5680 mRNA and 5740 miRNA expression profiles of 11 major human cancers were downloaded from the Cancer Genome Atlas (TCGA). The 11 cancer types were bladder urothelial carcinoma, breast invasive carcinoma, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and thyroid carcinoma. For each cancer type, we firstly obtained differentially expressed miRNAs (DEMs) and genes (DEGs) in tumor and then acquired critical miRNA-target gene pairs by combining DEMs, DEGs and two experimentally validated miRNA-target interaction databases, miRTarBase and miRecords. We collected samples with both miRNA and mRNA expression values and performed a correlation analysis by Pearson method for miRNA-target pairs in normal and tumor, respectively.
Results:
We totally got 4743 critical miRNA-target pairs across 11 cancer types, and 4572 of them showed weaker correlation in tumor than in normal. The average correlation coefficients of miRNA-target pairs were different greatly between normal (-0.38 ~ -0.61) and tumor (-0.04 ~ -0.26) for 11 cancer type. The pan-cancer network, which consisted of 108 edges connecting 35 miRNAs and 89 target genes, showed the interactions of pairs appeared in multicancers.
Conclusions:
This comprehensive analysis revealed that correlation between miRNAs and target genes was greatly reduced in tumor and these critical pairs we got were involved in cellular adhesion, proliferation, and migration. Our research could provide opportunities for investigating cancer molecular regulatory mechanism and seeking therapeutic targets.
... Increased Anoikis, apoptosis due to loss of anchorage to extracellular matrix, was observed in pancreatic carcinoma cells when the GNE gene was silenced. Additionally, the level of CHOP has been reported to increase in GNE deficient cells indicative of apoptosis through ATF4-ATF3-CHOP pathway (Kemmner et al., 2012). Increased apoptosis due to internalization of Aβ peptides in hyposialylated C2C12 myotubes and skeletal muscles was observed in the patients of GNEM (Bosch-Morató et al., 2016). ...
Age is the common risk factor for both neurodegenerative and neuromuscular diseases. Alzheimer disease (AD), a neurodegenerative disorder, causes dementia with age progression while GNE myopathy (GNEM), a neuromuscular disorder, causes muscle degeneration and loss of muscle motor movement with age. Individuals with mutations in presenilin or amyloid precursor protein (APP) gene develop AD while mutations in GNE (UDP N-acetylglucosamine 2 epimerase/N-acetyl Mannosamine kinase), key sialic acid biosynthesis enzyme, cause GNEM. Although GNEM is characterized with degeneration of muscle cells, it is shown to have similar disease hallmarks like aggregation of Aβ and accumulation of phosphorylated tau and other misfolded proteins in muscle cell similar to AD. Similar impairment in cellular functions have been reported in both disorders such as disruption of cytoskeletal network, changes in glycosylation pattern, mitochondrial dysfunction, oxidative stress, upregulation of chaperones, unfolded protein response in ER, autophagic vacuoles, cell death, and apoptosis. Interestingly, AD and GNEM are the two diseases with similar phenotypic condition affecting neuron and muscle, respectively, resulting in entirely different pathology. This review represents a comparative outlook of AD and GNEM that could lead to target common mechanism to find a plausible therapeutic for both the diseases.
... Increased Anoikis, apoptosis due to loss of anchorage to extracellular matrix, was observed in pancreatic carcinoma cells when the GNE gene was silenced. Additionally, the level of CHOP has been reported to increase in GNE deficient cells indicative of apoptosis through ATF4-ATF3-CHOP pathway (Kemmner et al., 2012). Increased apoptosis due to internalization of Aβ peptides in hyposialylated C2C12 myotubes and skeletal muscles was observed in the patients of GNEM (Bosch-Morató et al., 2016). ...
... The observation that GNE activity affects N-linked glycan branching adds to a growing body of literature identifying noncanonical roles for GNE (35)(36)(37)(38). Some non-canonical roles appear to be independent of sialic acid synthesis (37) and may depend on the ability of GNE to engage in protein-protein interactions (36). ...
GNE myopathy is a rare muscle disorder associated with aging and is related to sporadic inclusion body myositis (sIBM), the most common acquired muscle disease of aging. While the cause of sIBM is unknown, GNE myopathy is associated with mutations in UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). GNE harbors two enzymatic activities required for biosynthesis of sialic acid in mammalian cells. Mutations to both GNE domains are linked to GNE myopathy. However, correlation between mutation-associated reductions in sialic acid production and disease severity is imperfect. To investigate other potential effects of GNE mutations, we compared sialic acid production in cell lines expressing wild-type or mutant forms of GNE. Although we did not detect any differences attributable to disease-associated mutations, lectin binding and mass spectrometry analysis revealed that GNE deficiency is associated with unanticipated effects on the structure of cell-surface glycans. In addition to exhibiting low levels of sialylation, GNE-deficient cells produced distinct N-linked glycan structures with increased branching and extended poly-N-acetyllactosamine (polyLacNAc). GNE deficiency may affect levels of UDP-GlcNAc, a key metabolite in the nutrient-sensing hexosamine biosynthetic pathway, but this modest effect did not fully account for the change in N-linked glycan structure. Further, GNE deficiency and glucose supplementation acted independently and additively to increase N-linked glycan branching. Notably, N-linked glycans produced by GNE-deficient cells displayed enhanced binding to galectin-1, indicating that changes in GNE activity can alter affinity of cell-surface glycoproteins for the galectin lattice. These findings suggest an unanticipated mechanism by which GNE activity might affect signaling through cell-surface receptors.
... We also found patients with low GNE expression levels had poor recurrence-free survival probability (Log-rank P = 1.02e−02, Figure 5D). GNE dysregulation occurred predominantly in pancreatic cancer but also in other malignancies [36]. Among the differentially expressed genes in metastatic samples, we found 7 of 30 genes (MAPK13, XIAP, AHR, SPN, TER1, EMP2, NDUFC2) were cancer-related (Supplementary Figure S10, Supplementary Table S13). ...
RNA editing results in post-transcriptional modification and could potentially contribute to carcinogenesis. However, RNA editing in advanced lung adenocarcinomas has not yet been studied. Based on whole genome and transcriptome sequencing data, we identified 1,071,296 RNA editing events from matched normal, primary and metastatic samples contributed by 24 lung adenocarcinoma patients, with 91.3% A-to-G editing on average, and found significantly more RNA editing sites in tumors than in normal samples. To investigate cancer relevant editing events, we detected 67,851 hyper-editing sites in primary and 50,480 hyper-editing sites in metastatic samples. 46 genes with hyper-editing in coding regions were found to result in amino acid alterations, while hundreds of hyper-editing events in non-coding regions could modulate splicing or gene expression, including genes related to tumor stage or clinic prognosis. Comparing RNA editome of primary and metastatic samples, we also discovered hyper-edited genes that may promote metastasis development. These findings showed a landscape of RNA editing in matched normal, primary and metastatic tissues of lung adenocarcinomas for the first time and provided new insights to understand the molecular characterization of this disease.
... CCL28, which encodes the growth factor chemokine ligand 28 [45], increases placental cell apoptosis [46] and is downregulated in a variety of human malignancies [47,48]. GNE encodes a key enzyme in sialic acid biosynthesis, a process that is often upregulated in tumor development [49]. Reduced sialylation has been shown in heterozygous Gne-deficient mice, while complete knockouts are embryonically lethal [50]. ...
Background
Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta.
Results
We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort.
Conclusions
Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt signaling. We show that monozygotic monochorionic twins discordant for growth provide a useful model to study one type of the epigenetic placental dysregulation that drives IUGR.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0238-x) contains supplementary material, which is available to authorized users.
