HERV-K and HERV-H Env Proteins Induce a Humoral Response in Prostate Cancer Patients.
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ABSTRACT:
SUBMITTER: Manca MA
PROVIDER: S-EPMC8778306 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The vertebrate genome contains an endogenous retrovirus that has been inherited from the past millions of years. Although approximately 8% of human chromosomal DNA consists of sequences derived from human endogenous retrovirus (HERV) fragments, most of the HERVs are currently inactive and noninfectious due to recombination, deletions, and mutations after insertion into the host genome. Several studies suggested that Human endogenous retroviruses (HERVs) factors are significantly related to certain cancers. However, only limited studies have been conducted to analyze the expression of HERV derived elements at protein levels in certain cancers. Herein, we analyzed the expression profiles of HERV-K envelope (Env) and HERV-R Env proteins in eleven different kinds of cancer tissues. Furthermore, the expression patterns of both protein and correlation with various clinical data in each tissue were analyzed. The expressions of both HERV-K Env and HERV-R Env protein were identified to be significantly high in most of the tumors compared with normal surrounding tissues. Correlations between HERV Env expressions and clinical investigations varied depending on the HERV types and cancers. Overall expression patterns of HERV-K Env and HERV-R Env proteins were different in every individual but a similar pattern of expressions was observed in the same individual. These results demonstrate the expression profiles of HERV-K and HERV-R Env proteins in various cancer tissues and provide a good reference for the association of endogenous retroviral Env proteins in the progression of various cancers. Furthermore, the results elucidate the relationship between HERV-Env expression and the clinical significance of certain cancers. [BMB Reports 2021; 54(7): 368-373].
| S-EPMC8328825 | biostudies-literature
Project description:BackgroundThe etiology of the neurogenerative disease multiple sclerosis (MS) is unknown. The leading hypotheses suggest that MS is the result of exposure of genetically susceptible individuals to certain environmental factor(s). Herpesviruses and human endogenous retroviruses (HERVs) represent potentially important factors in MS development. Herpesviruses can activate HERVs, and HERVs are activated in MS patients.ResultsUsing flow cytometry, we have analyzed HERV-H Env and HERV-W Env epitope expression on the surface of PBMCs from MS patients with active and stable disease, and from control individuals. We have also analyzed serum antibody levels to the expressed HERV-H and HERV-W Env epitopes. We found a significantly higher expression of HERV-H and HERV-W Env epitopes on B cells and monocytes from patients with active MS compared with patients with stable MS or control individuals. Furthermore, patients with active disease had relatively higher numbers of B cells in the PBMC population, and higher antibody reactivities towards HERV-H Env and HERV-W Env epitopes. The higher antibody reactivities in sera from patients with active MS correlate with the higher levels of HERV-H Env and HERV-W Env expression on B cells and monocytes. We did not find such correlations for stable MS patients or for controls.ConclusionThese findings indicate that both HERV-H Env and HERV-W Env are expressed in higher quantities on the surface of B cells and monocytes in patients with active MS, and that the expression of these proteins may be associated with exacerbation of the disease.
| S-EPMC2780989 | biostudies-literature
Project description:ObjectivesThe effect of concomitant steroid use on the antibody response to a SARS-CoV-2 vaccine in patients with prostate cancer (PC) remains unknown. We aimed to evaluate the rates of antispike immunoglobulin G (IgG) antibody response to the BNT162b2 mRNA vaccine in patients with PC using steroids.MethodsThis cross-sectional study conducted from June 21, 2021 to January 5, 2022 included 215 patients with PC who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of titers of IgG antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein. We compared the rate of anti-SARS-CoV-2 S IgG ≥15 U/mL between patients with or without concomitant steroid use.ResultsOf 215, we identified 33 patients who had concomitant steroid use. Of these, 12 and 21 patients were metastatic castration-sensitive PC and castration-resistant PC (CRPC), respectively. Patients with concomitant steroid use had a significantly lower rate of antibody titer ≥15 U/mL than those without steroid use (82% vs. 95%, P = 0.021). Patients with CRPC with concomitant steroid use (n =21) also had a lower rate of antibody titer ≥15 U/mL (71%) than those without steroid use (93%, P = 0.051), although this was not statistically different. Increased number of systemic treatments administered after diagnosis of CRPC (3 lines or more) were significantly associated with antibody titers <15 U/mL (97% vs. 77%, P <0.001).ConclusionThe humoral response to the BNT162b2 mRNA vaccine was significantly lower in patients with concomitant steroid use. Anti-SARS-CoV-2 S antibody titers were affected by CRPC status, the accumulation of post-CRPC treatments, and steroid use.
| S-EPMC9339980 | biostudies-literature
Project description:Background:A specific humoral immune response against HERV-W envelope surface (env-su) glycoprotein antigens has been reported in serum of patients with multiple sclerosis (MS). However, it has not been evaluated to date in patients with neuromyelitis optica spectrum disorder (NMOSD). Objective:The objective of this paper is to investigate whether antibody (Ab) response against HERV-W env-su antigenic peptides differs between NMOSD and MS. Methods:Serum samples were collected from 36 patients with NMOSD, 36 patients with MS and 36 healthy control individuals (HCs). An indirect ELISA was set up to detect specific Abs against HERV-W env-su peptides. Results:Our data showed that two antigenic peptides, particularly HERV-Wenv93-108 and HERV-Wenv248-262, were statistically significantly present only in serum of MS compared to NMOSD and HCs. Thus, the specific humoral immune response against HERV-W env-su glycoprotein antigens found in MS is widely missing in NMOSD. Conclusion:Increased circulating serum levels of these HERV-W Abs may be suitable as additional biomarkers to better differentiate MS from NMOSD.
| S-EPMC5703109 | biostudies-literature
Project description:Human endogenous retrovirus type K (HERV-K) Env protein was previously demonstrated to be overexpressed in human breast cancer (BC) cells and tissues. However, the molecular pathways driving the specific alterations are unknown. We now show that knockdown of its expression with an shRNA (shRNAenv) blocked BC cell proliferation, migration, and invasion. shRNAenv transduction also attenuated the ability of BC cells to form tumors, and notably prevented metastasis. Mechanistically, downregulation of HERV-K blocked expression of tumor-associated genes that included Ras, p-RSK, and p-ERK. The major upstream regulators influenced by HERV-K knockdown were p53, TGF- β1, and MYC. Of interest, when the HERV-K env gene was overexpressed in shRNAenv-transduced BC cells using an HERV-K env expression vector, Ras/Raf/MEK/ERK pathway signaling was restored. CDK5, which alters p53 phosphorylation in some cancers, was upregulated and p53 was downregulated when HERV-K was overexpressed. CDK5 is also a mediator of TGF-β1-induced epithelial-mesenchymal transition and migration in cancer cells, and is involved in tumor formation. Importantly, reductions in migration, invasion, and transformation of BC cells stably transduced with shRNAenv was reversed after adding back a vector with a synonymous mutation of HERV-K env. Taken together, these results indicate that HERV-K Env protein plays an important role in tumorigenesis and metastasis of BC.
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Project description:Transcriptome analysis revealed that 23 differentially expressed genes (DEGs) were upregulated and 17 DEGs were downregulated in SKOV3 cells. In OVCAR3 cells, 198 DEGs were upregulated, and 17 DEGs were downregulated. Notably, 53 DEGs exhibited statistically significant differences among the 1,612 DEGs identified. Our findings indicate that HERV-K env gene KO exerts a profound influence on gene expression patterns in OVCAR3 cells, while genetic alterations in expression were relatively modest in SKOV3 cells. Nevertheless, genes ND1, ND2, and CYTB displayed a common increase in expression, while ERRFI1 and NDRG1 exhibited a decrease in expression in both cell lines.
2024-10-31 | GSE269969 | GEO
Project description:Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ (n = 17), MG-MuSK Ab+ (n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + (n = 4), and one patient with no antibodies data (n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su(19-37), HERV-K-env-su(109-126), HERV-K-env-su(164-186), HERV-W-env(93-108), HERV-W-env(129-14), and HERV-W-env(248-262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population.
| S-EPMC10778599 | biostudies-literature
Project description:In this study, recombinant Fc-fused Prostate acid phosphatase (PAP) proteins were produced in transgenic plants. PAP was fused to immunoglobulin (Ig) A and M Fc domain (PAP-IgA Fc and PAP-IgM Fc), which were tagged to the ER retention sequence KDEL to generate PAP-IgA FcK and PAP-IgM FcK. Agrobacteriummediated transformation was performed to produce transgenic tobacco plants expressing four recombinant proteins. Genomic PCR and RT-PCR analyses confirmed the transgene insertion and mRNA transcription of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK in tobacco plant leaves. Western blot confirmed the expression of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK proteins. SEC-HPLC and Bio-TEM analyses were performed to confirm the size and shape of the plant-derived recombinant PAP-Fc fusion proteins. In mice experiments, the plant-derived IgA and IgM Fc fused proteins induced production of total IgGs including IgG1 against PAP. This result suggests that IgA and IgM Fc fusion can be applied to produce recombinant PAP proteins as a prostate cancer vaccine in plant expression system. [BMB Reports 2023; 56(7): 392-397].
| S-EPMC10390288 | biostudies-literature
Project description:High-density phage epitope microarray from 31 samples were used for unsupervised analysis (GSM36153...GSM36183). 129 samples from prostate cancer patients and controls were screened on small focused epitope chips, which contained 180 phage elements. These data were used to train GA/KNN program (GSM36184...GSM36312). 128 samples from localized prostate cancer patients and controls were screened on small focused epitope chips. These independent data were used to validate the epitomic profile (GSM36313...GSM36375, GSM40203...GSM40213, GSM40216, GSM40218, GSM40219, GSM40222, GSM40225, GSM40227, GSM40229, GSM40233, GSM40237, GSM40246...GSM40294). Three subgroups of samples were used as test sets to validate the specificity of epitomic profile (GSM36376...GSM36410, GSM40214, GSM40215, GSM40217, GSM40220, GSM40221, GSM40224, GSM40226, GSM40228, GSM40231, GSM40234...GSM40236, GSM40238...GSM40244). Project----Identification of humoral signature for prostate cancer diagnosis We constructed a prostate cancer cDNA phage display library. cDNAs were reverse-synthesized from mDNA pool isolated from prostate cancer tissues. Enzyme-digested cDNA fragments were then inserted into phage vector to make a whole prostate cancer phage expressed cDNA library. In order to select cancer specific phage epitope from this library, we performed several cycles of affinity enrichment. We used the bounded IgG pool isolated from prostate cancer patient sera to select the tumor specific phage epitope clones. Once we had the enriched phage epitope library, we cultured the phage library on LB-agar dish for individual phage colonies. About 2300 phage colonies from agar dish were picked up using toothstick and cultured in 96-well microtiter plates. Each clone was labeled as microtiter plate #, column #, row#, i.e. clone ID. These 2300 clones were then spotted on slides in single spot (no any duplicate), i.e. each spot (labeled by clone ID) represents a single phage clone. The phage epitope microarrays were then screened using cancer or control sera. We employed two color system. Cy5-anti human IgG was to detect human IgG. For green color, we used Cy3-labeled anti-phage capsid protein as internal reference to normalize the ammount difference of phage particles spotted on each spot. Thus the ratio of Cy5/Cy3 would count for the immune response in cancer or control sera. Once we identified humoral signature in prostate cancer patients, we could sequence the phage clone to characterize the nature of the genes or proteins.
2005-10-04 | E-GEOD-2010 | biostudies-arrayexpress
Project description:Human Endogenous Retroviruses (HERVs) are exogenous viral elements that integrated into the germline millions of years ago. They comprise 8% of the human genome and play a critical role in cellular differentiation during development. HERV-K(HML-2) is the most recently integrated and actively transcribed HERV. It is found to be highly expressed in pluripotent stem cells and strongly downregulated during cellular differentiation. Moreover, expression of HERV-K in terminally differentiated neurons results in cytotoxicity. Expression of HERVs has been implicated in carcinogenesis and is suggested to confer stem cell like features important for cell growth. Atypical Teratoid / Rhabdoid Tumor (AT/RT) is a rare pediatric brain cancer that results from incomplete neuronal differentiation during embryonic development. In this paper, we investigated the cytopathic effect of Ouabain, a cardiac glycoside that induces cytotoxicity in stem cells, on AT/RT cells. We characterized four AT/RT cell lines by immunostaining and observed variable levels of stem cell, Oct4 and Pax6, and neuronal differentiation markers, TUBB3 and MAP2, as well as HERV-K envelope (env), polymerase (pol), and gag transcripts. We stained formalin-fixed brain tissues from 20 AT/RT patients and 5 unaffected controls for HERV-K ENV protein expression. 40% of AT/RT patient tissues showed ENV expression. In contrast, no ENV immunostaining was observed in all 5 control brain tissues. We used Ouabain, known to be cytotoxic to stem cells, observed up to 50% toxicity at 24 hr and 80% toxicity at 48 hr after treatment. While AT/RT primarily exist as large cell aggregates in suspension, Ouabain treatment downregulated HERV-K ENV protein and caused disruption of cell-to-cell interactions. Similarly, when AT/RT cells were transfected with a CRISPR/Cas9 construct designed to repress HERV-K promotor activity, cell aggregates separated and cell viability decreased significantly. Using a luciferase reporter construct under the control of a HERV-K promotor, we observed a significant decrease in HERV-K promotor activity at 8 to 72 hr post treatment with 0.5 uM Ouabain. Given that downregulation of HERV-K alone was sufficient to cause cytotoxicity in the cells, HERV-K expression may be essential for AT/RT growth and survival. Ouabain and other compounds that modulate HERV expression may provide an alternative or adjunctive therapeutic option for treatment of embryonal tumors.
2021-06-28 | GSE124210 | GEO