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British Journal of Cancer Jul 2005Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations... (Review)
Review
Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations critical to the normal physiological functioning of cells, such as alterations of growth factor signalling pathways, angiogenesis, cell adhesion signals, DNA replication and apoptotic cell death. Many genes involved in the processes enumerated above are functionally inactive in tumour cells, designating them as putative 'tumour suppressor genes'. Back in the early 1990s, Vogelstein and colleagues suggested that a gene called DCC (for Deleted in Colorectal Cancer) could be a tumour suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last 15 years, controversial data have failed to firmly establish whether DCC is indeed a tumour suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis, have prompted a renewal of interest in the role of DCC in tumorigenesis and suggest that the netrin-1/receptor pairs act as novel negative regulators of tumour development.
Topics: Colorectal Neoplasms; Genes, DCC; Genes, Tumor Suppressor; Humans; Nerve Growth Factors; Netrin Receptors; Netrin-1; Receptors, Cell Surface; Tumor Suppressor Proteins
PubMed: 15956977
DOI: 10.1038/sj.bjc.6602656 -
Developmental Medicine and Child... Jun 2020Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we...
Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.
Topics: Adolescent; Adult; Agenesis of Corpus Callosum; Child; Cohort Studies; DCC Receptor; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Movement Disorders; Mutation; Neuropsychological Tests; Prognosis; Young Adult
PubMed: 32060908
DOI: 10.1111/dmcn.14486 -
Biological Psychiatry May 2021Adolescence is a period of increased vulnerability to psychiatric disorders, including depression. Discovering novel biomarkers to identify individuals who are at high...
BACKGROUND
Adolescence is a period of increased vulnerability to psychiatric disorders, including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood by targeting the netrin-1 guidance cue receptor gene Dcc in the medial prefrontal cortex (mPFC).
METHODS
Here, we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability in male mice.
RESULTS
miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood.
CONCLUSIONS
miR-218 expression in adolescence may serve both as a marker of risk and as a target for early interventions.
Topics: Animals; Down-Regulation; Male; Mice; MicroRNAs; Prefrontal Cortex; Social Behavior; Stress, Psychological
PubMed: 33384174
DOI: 10.1016/j.biopsych.2020.10.015 -
Genes & Development May 1994The analysis of human colorectal tumors has revealed frequent loss of heterozygosity (LOH) of the long arm of chromosome 18. A novel gene, DCC (deleted in colorectal...
The analysis of human colorectal tumors has revealed frequent loss of heterozygosity (LOH) of the long arm of chromosome 18. A novel gene, DCC (deleted in colorectal cancer), located within the region of LOH on chromosome 18q was identified and has been implicated as a tumor suppressor gene. We have now shown that DCC encodes a membrane-bound protein of the immunoglobulin-CAM family, as demonstrated by cell-surface labeling, immunohistochemical analysis, and sequencing of cDNA clones. The DCC protein was found in axons of the central and peripheral nervous system and in differentiated cell types of the intestine. Colorectal tumors that lost their capacity to differentiate into mucus producing cells uniformly lacked DCC expression and loss of a chromosome 18q allele was often accompanied by loss of DCC expression in colon tumors. These results provide evidence that DCC encodes a cell surface-localized protein and emphasize the inverse relationship between differentiation and tumorigenesis.
Topics: Adenocarcinoma, Mucinous; Adenoma; Adenomatous Polyps; Animals; Carcinoma; Cell Adhesion Molecules; Cell Differentiation; Cell Transformation, Neoplastic; Colorectal Neoplasms; DCC Receptor; DNA, Complementary; Gene Expression Regulation, Neoplastic; Genes, DCC; Humans; Intestinal Polyps; Molecular Sequence Data; Open Reading Frames; Organ Specificity; RNA, Messenger; Rats; Receptors, Cell Surface; Recombinant Fusion Proteins; Tumor Cells, Cultured; Tumor Suppressor Proteins
PubMed: 7926722
DOI: 10.1101/gad.8.10.1174 -
PloS One 2023Current immunological issues in bone grafting regarding the transfer of xenogeneic donor bone cells into the recipient are challenging the industry to produce safer...
Current immunological issues in bone grafting regarding the transfer of xenogeneic donor bone cells into the recipient are challenging the industry to produce safer acellular natural matrices for bone regeneration. The aim of this study was to investigate the efficacy of a novel decellularization technique for producing bovine cancellous bone scaffold and compare its physicochemical, mechanical, and biological characteristics with demineralized cancellous bone scaffold in an in-vitro study. Cancellous bone blocks were harvested from a bovine femoral head (18-24 months old) subjected to physical cleansing and chemical defatting, and further processed in two ways. Group I was subjected to demineralization, while Group II underwent decellularization through physical, chemical, and enzymatic treatments. Both were then freeze-dried, and gamma radiated, finally producing a demineralized bovine cancellous bone (DMB) scaffold and decellularized bovine cancellous bone (DCC) scaffold. Both DMB and DCC scaffolds were subjected to histological evaluation, scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS), fourier-transform infrared spectroscopy (FTIR), quantification of lipid, collagen, and residual nucleic acid content, and mechanical testing. The osteogenic potential was investigated through the recellularization of scaffolds with human osteoblast cell seeding and examined for cell attachment, proliferation, and mineralization by Alizarin staining and gene expression. DCC produced a complete acellular extracellular matrix (ECM) with the absence of nucleic acid content, wider pores with extensive interconnectivity and partially retaining collagen fibrils. DCC demonstrated a higher cell proliferation rate, upregulation of osteogenic differentiation markers, and substantial mineralized nodules production. Our findings suggest that the decellularization technique produced an acellular DCC scaffold with minimal damage to ECM and possesses osteogenic potential through the mechanisms of osteoconduction, osteoinduction, and osteogenesis in-vitro.
Topics: Animals; Cattle; Humans; Infant; Child, Preschool; Osteogenesis; Tissue Scaffolds; Tissue Engineering; Cancellous Bone; Collagen; Nucleic Acids; Cell Differentiation
PubMed: 37018321
DOI: 10.1371/journal.pone.0283922 -
Scientific Reports Feb 2017Understanding the loss of conserved genes is critical for determining how phenotypic diversity is generated. Here we focus on the evolution of DCC, a gene that encodes a...
Understanding the loss of conserved genes is critical for determining how phenotypic diversity is generated. Here we focus on the evolution of DCC, a gene that encodes a highly conserved neural guidance receptor. Disruption of DCC in animal models and humans results in major neurodevelopmental defects including commissural axon defects. Here we examine DCC evolution in birds, which is of particular interest as a major model system in neurodevelopmental research. We found the DCC containing locus was disrupted several times during evolution, resulting in both gene losses and faster evolution rate of salvaged genes. These data suggest that DCC had been lost independently twice during bird evolution, including in chicken and zebra finch, whereas it was preserved in many other closely related bird species, including ducks. Strikingly, we observed that commissural axon trajectory appeared similar regardless of whether DCC could be detected or not. We conclude that the DCC locus is susceptible to genomic instability leading to independent disruptions in different branches of birds and a significant influence on evolution rate. Overall, the phenomenon of loss or molecular evolution of a highly conserved gene without apparent phenotype change is of conceptual importance for understanding molecular evolution of key biological processes.
Topics: Animals; Birds; Evolution, Molecular; Genes, DCC; Genetic Loci; Genomic Instability
PubMed: 28240293
DOI: 10.1038/srep42029 -
Journal of Clinical Laboratory Analysis Apr 2022The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130...
BACKGROUND
The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals.
METHODS
The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction.
RESULTS
The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05).
CONCLUSIONS
Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.
Topics: ADAMTS Proteins; Carcinogenesis; Chemokines; Female; Genes, Tumor Suppressor; Humans; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MARVEL Domain-Containing Proteins; Male; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis
PubMed: 35176183
DOI: 10.1002/jcla.24289 -
PLoS Genetics Apr 2021Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of,... (Meta-Analysis)
Meta-Analysis
Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.
Topics: Biological Specimen Banks; Chronic Pain; Female; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Sex Characteristics; United Kingdom
PubMed: 33830993
DOI: 10.1371/journal.pgen.1009428 -
Genomics Feb 1994DCC is a candidate tumor-suppressor gene encoding a protein with sequence similarity to cell adhesion molecules such as N-CAM. A set of overlapping YAC clones that...
DCC is a candidate tumor-suppressor gene encoding a protein with sequence similarity to cell adhesion molecules such as N-CAM. A set of overlapping YAC clones that contains the entire DCC coding region was isolated. Studies of this YAC contig showed that the DCC gene spans approximately 1.4 Mb. For elucidation of exon-intron structure, lambda phage clones containing all known coding sequences were isolated from a genomic library. These clones were used to demonstrate the existence of 29 DCC exons, and the sequences of the exon-intron boundaries were determined for each. Twenty-three polymorphic markers from chromosome 18 were then studied in a panel of primary colorectal tumors that had lost some, but not all, of chromosome 18. In most of these tumors, the region that was lost included DCC. Finally, Southern blot and PCR-based approaches were used to search for subtle mutations in several DCC exons. One tumor that had a point mutation in exon 28 was found, resulting in a proline to histidine substitution. A second tumor with a point mutation in intron 13 was also found. The regional map and genomic structure of DCC should provide the means to more extensively study DCC gene alterations and protein function in normal and neoplastic cells.
Topics: Amino Acid Sequence; Base Sequence; Chromosomes, Artificial, Yeast; Chromosomes, Human, Pair 18; Colorectal Neoplasms; Consensus Sequence; DNA Mutational Analysis; DNA, Neoplasm; Exons; Genes, DCC; Genetic Markers; Humans; Molecular Sequence Data; Mutation; Point Mutation; Sequence Deletion
PubMed: 8188295
DOI: 10.1006/geno.1994.1102 -
The American Journal of Pathology Feb 2022Next-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased...
Next-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased understanding of disease. miRNAs are small regulatory RNA molecules that can be quantified using next-generation sequencing and are excellent classificatory markers. Herein, a deep cancer classifier (DCC) was adapted to differentiate neoplastic from nonneoplastic samples using comprehensive miRNA expression profiles from 1031 human breast and skin tissue samples. The classifier was fine-tuned and evaluated using 750 neoplastic and 281 nonneoplastic breast and skin tissue samples. Performance of the DCC was compared with two machine-learning classifiers: support vector machine and random forests. In addition, performance of feature extraction through the DCC was also compared with a developed feature selection algorithm, cancer specificity. The DCC had the highest performance of area under the receiver operating curve and high performance in both sensitivity and specificity, unlike machine-learning and feature selection models, which often performed well in one metric compared with the other. In particular, deep learning had noticeable advantages with highly heterogeneous data sets. In addition, our cancer specificity algorithm identified candidate biomarkers for differentiating neoplastic and nonneoplastic tissue samples (eg, miR-144 and miR-375 in breast cancer and miR-375 and miR-451 in skin cancer).
Topics: Breast Neoplasms; Female; Gene Expression Profiling; Humans; Machine Learning; MicroRNAs; RNA, Neoplasm
PubMed: 34774515
DOI: 10.1016/j.ajpath.2021.10.012