Regulation of dendritic cell genes by alpha fetoprotein
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE62005 | GEO | 2014/12/23
SECONDARY ACCESSION(S): PRJNA262924
REPOSITORIES: GEO
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Project description:Human dendritic cells (DC) are suppressed by tumor-derived alpha fetoprotein (AFP), but less so by cord blood-derived normal AFP. We tested human DC from 5 healthy donors for transcriptional changes induced by tumor (tAFP) or cord blood (nAFP) AFP, vs. chicken ovalbumin (OVA) control.
2014-12-23 | E-GEOD-62005 | biostudies-arrayexpress
Project description:Alpha fetoprotein (AFP) is a circulating cancer biomarker implicated in multiple neoplastic malignancies, including hepatocellular carcinoma (HCC). AFP glycoforms with core fucosylation structure (AFP-L3) are used clinically as a biomarker, to predict risk of developing HCC and to monitor its recurrence. Mature AFP has a single glycosylation site, while there is a high degree of structural variation in AFP-glycan modifications. Because AFP has single glycosylation site, masses of intact AFP proteoforms can be used to differentiate and identify PTM in their native states. We developed a method for intact AFP glycoform analysis that utilizes AFP-specific immune-enrichment, followed by LC-high resolution mass spectrometry (LC-HRMS) analysis to differentiate and quantitate the relative abundance of AFP glycoforms and evaluated the method’s performance.
2023-01-11 | PXD038606 | Pride
Project description:Glycosylation is an important post-translational modification (PTM) mechanism of proteins, that modulates protein function. Measurement of clinically adopted cancer protein biomarkers is commonly performed using affinity-based techniques, which often suffer from poor specificity and inability to distinguish between closely related proteoforms. Alpha fetoprotein (AFP) is a circulating cancer biomarker implicated in multiple neoplastic malignancies, including hepatocellular carcinoma (HCC). AFP glycoforms with core fucosylation structure (AFP-L3) are used clinically as a biomarker, to predict risk of developing HCC and to monitor its recurrence. Mature AFP has a single glycosylation site, while there is a high degree of structural variation in AFP-glycan modifications. Because AFP has single glycosylation site, masses of intact AFP proteoforms can be used to differentiate and identify PTM in their native states. We developed a method for intact AFP glycoform analysis that utilizes AFP-specific immune-enrichment, followed by LC-high resolution mass spectrometry (LC-HRMS) analysis to differentiate and quantitate the relative abundance of AFP glycoforms and evaluated the method’s performance.
2023-01-11 | PXD038602 | Pride
Project description:Individuals exposed to Mycobacterium tuberculosis (Mtb) may become infected and are classified as with latent tuberculosis infection (LTBI) and remain whole time life in this condition or develop active tuberculosis (TB). Among the multiple factors governing the outcome of the infection, dendritic cells (DC) play a major role in dictating protective immunity. However, current knowledge on the role of the diverse components of human DC in shaping specific T cell response during Mtb infection is limited. In this study, we performed a comparative evaluation of peripheral blood circulating DC subsets along with the functional capability of monocyte-derived IFN-α DC to induce Mtb antigen-specific T cell response in patients with active TB, subjects with LTBI and healthy donors (HD). The percentage of BDCA3+ mDC2 and CD123+ pDC declined significantly in active TB patients with respect HD whereas the same subsets displayed a remarkable activation in LTBI. Simultaneously, IFN-α-driven differentiation of DC resulted profoundly impaired from monocytes of active TB patients as compared to LTBI and HD individuals. Importantly, the specific altered developmental trait of IFN-α DC from active TB patients was associated with a marked change of molecular signalings conveying antigen presentation as well as full inability to induce antigen-specific T cell response. Thus, these data unravel an unavoidable role of IFN-α in determining the induction of Mtb-specific protective immunity which is essential to control Mtb infection.
2017-12-18 | GSE84344 | GEO
Project description:Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Using microarray-based global microRNA profiling in 223 HCC patients, we found that members of the miR-29 family were the most significantly (p<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (p<0.001) between miR-29 and DNMT3A gene expression suggesting that they might be functionally antagonistic. Moreover, global DNA methylation array profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Interestingly, miR-29 family physiological expression is low in mouse embryonic livers but gradually increases after birth. This is in contrary to AFP expression, which dramatically decreases after birth. Experimentally, we demonstrated that increased AFP expression, or conditioned media from AFP expressing HCC cells, inhibits miR-29a expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus and this effect is mediated through c-MYC binding to the miR-29a/b-1 promoter. Our findings indicate that tumor biology differs considerably between AFP+ HCC and AFP- HCC and that AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC. Illumina Human BeadChip Methylation microarrays were completed on 48 tumor HCC tissues.
2014-09-23 | E-GEOD-52018 | biostudies-arrayexpress
Project description:Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Using microarray-based global microRNA profiling in 223 HCC patients, we found that members of the miR-29 family were the most significantly (p<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (p<0.001) between miR-29 and DNMT3A gene expression suggesting that they might be functionally antagonistic. Moreover, global DNA methylation array profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Interestingly, miR-29 family physiological expression is low in mouse embryonic livers but gradually increases after birth. This is in contrary to AFP expression, which dramatically decreases after birth. Experimentally, we demonstrated that increased AFP expression, or conditioned media from AFP expressing HCC cells, inhibits miR-29a expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus and this effect is mediated through c-MYC binding to the miR-29a/b-1 promoter. Our findings indicate that tumor biology differs considerably between AFP+ HCC and AFP- HCC and that AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.
2014-09-23 | GSE52018 | GEO
Project description:Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24â96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in macrophages. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. Experiment Overall Design: Microfilariae and human monocyte derived-DCs were cultuted at a multiplicity of infection of 1:1 for 24hrs for four independent donors. Matching samples exposed to media alone were used for controls The four experimental and 4 control samples were then pooled to create one experoimental and one healthy pool used for microarray analysis.
2008-10-25 | E-GEOD-12787 | biostudies-arrayexpress
Project description:Increased α-fetoprotein (AFP) levels have been reported to predict a poor prognosis in hepatocellular carcinoma (HCC). We assessed the mechanism of AFP involvement in the progression of HCC and determined whether AFP could be a molecular target. We used human HCC cell lines to assess proliferation and apoptosis response to exogenous AFP. We introduced AFP small interfering RNA (siRNA) into HCC cell lines to examine whether it could inhibit cell proliferation and anti-apoptotic properties. The effects of systemically introduced AFP siRNA were assessed using a tumor xenotransplantation model. The effects of AFP on gene expression in HCC cell lines and human HCC specimens were examined. Exogenous AFP induced cell proliferation dose-dependently and inhibited apoptosis induced by 5-fluorouracil (5-FU) in all cell lines examined. AFP siRNA inhibited the proliferation of AFP-producing HCC cell lines and induced apoptosis in co-cultures with 5-FU. Tumor sizes in mice treated with AFP siRNA were significantly smaller than those in controls. AFP siRNA administration in mice induced a low proliferation index and a high apoptosis index in tumors. cDNA microarray analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot using HepG2 and HLE cells with AFP showed that AFP reduced expression of genes related to apoptosis (DFFB) and tumor suppression (NDRG2). Expression of these molecules was also suppressed in human HCC tissues that overexpress AFP. AFP is not only a passive tumor marker, but also an active tumor stimulator through several mechanisms. AFP siRNA introduction may be of possible therapeutic use for HCC. Keywords: Genetic modification
2008-12-31 | GSE12307 | GEO
Project description:In mice, two restricted DC progenitors, macrophage-dendritic progenitor (MDP) and common dendritic cell progenitor (CDP) demonstrate increasing commitment of DC lineage as they sequentially lose granulocyte and monocyte potential respectively. Identifying these progenitors has enabled understanding of the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34+ hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, NK and B cells. Using this culture system we defined the pathway for human DC development, and revealed the sequential origin of human DCs from increasingly restricted progenitors: a granulocyte-monocyte-DC progenitor (hGMDP) that develops into a monocyte-DC progenitor (hMDP) that develops into monocytes and a common DC progenitor (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte monocyte progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues in the steady state. We performed whole transcriptome expression analysis on monocytes and subsets of dendritic cells i.e. CD1c+ DCs, CD141+ DCs and CD303+ pDCs isolated from blood or differentiated in culture from cord blood CD34+ cells in presence of MS5 stromal cells and Flt3l, GM-CSF and SCF cytokines.
2015-01-22 | E-GEOD-65128 | biostudies-arrayexpress
Project description:Functional characterization of human dendritic cell subsets is limited due to the very low frequency of these cells in vivo. We developed an in vitro culture system for the simultaneous generation of XCR1+ DCs and MoDCs from cord blood CD34+ cells. Their global gene expression profiles at steady state and under activation, phenotypes, morphologies and responses to different TLR ligands where characterized and compared with those of their in vivo counterparts. The study demonstrated that the XCR1+ DCs generated in vitro from cord blood CD34+ cells are equivalent to blood XCR1+ DCs and also allowed a rigorous comparison of this DC subset with MoDC which are often considered as the reference model for DCs. Altogether, our results showed that in vitro generated XCR1+ DCs are a better model for the study of blood DC than the conventionally used MoDCs. The different dendritic cell subsets used for the study were either generated in vitro from cord blood CD34+ cells with recombinant human cytokines or isolated from peripheral blood. The subsets were purified by fluorescence-activated cell sorting and their responses to PolyI:C, LPS or R848 were studied including by gene expression profiling.
2014-07-23 | E-GEOD-57671 | biostudies-arrayexpress