Auswahl der wissenschaftlichen Literatur zum Thema „Ervmer34“

Abstract Endogenous retroviruses (ERVs) are remnants of retroviral germline infections which occurred over the course of evolution and constitute between 5-8% of the human genome. Although ERV protein expression is typically silenced epigenetically in normal adult human tissues, previous studies have shown that some ERVSs, can be aberrantly expressed in multiple cancer types. This atypical expression of ERVs in tumors may represent a class of immunologically relevant tumor-associated antigens that can potentially be targeted clinically using therapeutic cancer vaccines. For the first time, this study evaluates the ERV envelope protein ERVMER34-1 as a potential target for a therapeutic cancer vaccine. We first assessed the expression of ERVMER34-1 in multiple tissues and found that ERVMER34-1 protein is absent in most healthy adult tissues and over expressed in multiple types of human carcinomas. ERVMER34-1 specific T-cells were detected in PBMCs of cancer patients but not healthy donors following an overnight stimulation. However, reactive T-cells are readily expanded from both healthy donor and cancer patient PBMCs following a 7-day in-vitro stimulation. Importantly, reactive CD8+ T cells selectively killed human carcinoma cells expressing the target antigen. Based on these findings, we rationally designed a ERVMER34-1 therapeutic cancer vaccine and assessed its immunogenicity and anti-tumor efficacy in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. Our rationally designed ERVMER34-1 cancer vaccine significantly mediated tumor regression and extended survival as a monotherapy and in combination with checkpoint blockade. Altogether, our work supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1 as a potential first-in-class immunotherapeutic target for the therapy of several carcinoma types. Citation Format: Maria Del Mar Maldonado, Masafumi Iida, Maria Del Mar Gracia Hernandez, Loc Le, Renee N. Donahue, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4092.

Abstract IDH1-wildtype (WT) GBMs are the most common and aggressive tumors of the central nervous system (CNS), with a median survival rate of 12-15 months, and are resistant to clinical therapies due to their heterogenous molecular phenotype. In this study, we developed a pipeline to dissect the potential role of human endogenous retroviruses (HERVs) in patient derived glioma stem cells (GSCs) and integrated our findings with published epigenomic datasets for enhancers (H3K27ac), CTCF, and chromatin toplogy (Hi-C). We found high expression of several HERV transcripts in IDH1-WT GBMs as compared to IDH1-mutant variants. Epigenomic analysis of these upregulated HERVs showed association with both enhancer marks and CTCF deposition. Annotation of HERVs to their nearest genes, followed by Gene Set Enrichment Analysis (GSEA), identified involvement of actin-filament based mechanisms and regulation of immune phenotype. Integration of these findings identified MER61 (ERVMER61-1), a potential regulator of Interleukin-6 and showed alteration in chromatin looping and enhancer occupancy. To summarize, our work points to novel mechanisms of GBM pathogenesis, through involvement of HERVs in cell migratory and immune dysfunction, warranting further investigations into these oncogenic mechanism to identify and develop novel therapeutic options for GBM.

The immune pathogenesis of multiple sclerosis (MS) is thought to be triggered by environmental factors in individuals with an unfavorable genetic predisposition. Epstein–Barr virus (EBV) infection is a major risk factor for subsequent development of MS. Human endogenous retroviruses (HERVs) can be activated by EBV, and might be a missing link between an initial EBV infection and the later onset of MS. In this study, we investigated differential gene expression patterns in EBV-immortalized lymphoblastoid B cell lines (LCL) from MS-affected individuals (MSLCL) and controls by using RNAseq and qRT-PCR. RNAseq data from LCL mapped to the human genome and a virtual virus metagenome were used to identify possible biomarkers for MS or disease-relevant risk factors, e.g., the relapse rate. We observed that lytic EBNA-1 transcripts seemed to be negatively correlated with age leading to an increased expression in LCL from younger PBMC donors. Further, HERV-K (HML-2) GAG was increased upon EBV-triggered immortalization. Besides the well-known transactivation of HERV-K18, our results suggest that another six HERV loci are up-regulated upon stimulation with EBV. We identified differentially expressed genes in MSLCL, e.g., several HERV-K loci, ERVMER61-1 and ERV3-1, as well as genes associated with relapses. In summary, EBV induces genes and HERV in LCL that might be suitable as biomarkers for MS or the relapse risk.

Introduction Breast cancer is the most common cancer and the leading cause of cancer death in women. Recent research indicates that human endogenous retroviruses (HERVs) may be linked to carcinogenesis, but the data remain controversial. Methods HERVs´ expression was evaluated to show the differences between breast cancer and control samples, and their associations with clinicopathological parameters. Gene expression of 12 HERVs, i.e. ERVE-4, ERVW-1, ERVFRD-1, ERVV-1, ERV3-1, ERVH48-1, ERVMER34-1, ERVK7, ERVK13-1, ERVK11-1, ERVK3-1 and HCP5 was analyzed by qPCR and/or TCGA datasets for breast cancer. Results ERV3-1, ERVFRD-1, ERVH48-1 and ERVW-1 provided data to support their tumor suppressor roles in breast cancer. ERV3-1 evinced the best performing diagnostic data based on qPCR, i.e. AUC: 0.819 (p <0.0001), sensitivity of 72.41%, and specificity of 89.66%. Lower levels of ERV3-1 were noted in advanced stage and higher grades, and significant negative association was found in relation to Ki-67 levels. Oncogenic roles may be inferred for ERVK13-1, ERVV-1, and ERVMER34-1. Data for ERVK-7, ERVE-4, ERVK11-1 and HCP5 remain inconclusive. Conclusion Differential HERVs expression may be applicable to evaluate novel biomarkers for breast cancer. However, more research is needed to reveal their real clinical impact, the biological roles and regulatory mechanisms in breast carcinogenesis.

Abstract At present, the etiology and pathogenesis of recurrent early pregnancy loss (REPL) are not completely clear. Therefore, identifying the underlying diagnostic and prognostic biomarkers of REPL can provide new ideas for the diagnosis and treatment of REPL. The chip data of REPL (GSE63901) were downloaded from the NCBI Gene Expression Omnibus (GEO) database. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to construct a co-expression module for studying the relationship between gene modules and clinical features. In addition, functional analysis of hub genes in modules of interest was performed. A total of 23 co-expression modules were identified, two of which were most significantly associated with three clinical features. The MEbrown module was positively correlated with cyclin E level and the out-of-phase trait while the MEred module was positively correlated with the effect of progesterone. We identified 17 hub genes in the MEred module. The functional enrichment analysis indicated that such hub genes were mainly involved in pathways related to cellular defense response and natural killer (NK) cell-mediated cytotoxicity. In the MEbrown module, we identified 19 hub genes, which were mainly enriched in cell adhesion molecule production, regulation of cellular response to growth factor stimulus, epithelial cell proliferation, and transforming growth factor-β (TGF-β) signaling pathway. In addition, the hub genes were validated by using other datasets and three true hub genes were finally obtained, namely DOCK2 for the MEred module, and TRMT44 and ERVMER34-1 for the MEbrown module. In conclusion, our results screened potential biomarkers that might contribute to the diagnosis and treatment of REPL.

Abstract Background Colon adenocarcinoma (COAD) patients who develop recurrence have poor prognosis. Our study aimed to establish effective prognosis prediction model based on competing endogenous RNAs (ceRNAs) for recurrence of COAD. Methods COAD expression profilings downloaded from The Cancer Genome Atlas (TCGA) were used as training dataset, and expression profilings of GSE29623 retrieved from Gene Expression Omnibus (GEO) were set as validation dataset. Differentially expressed RNAs (DERs) between non-recurrent and recurrent specimens in training dataset were screened, and optimum prognostic signature DERs were revealed to establish prognostic score (PS) model. Kaplan-Meier survival analysis was conducted for PS model, and GEO dataset was used for validation. Prognosis prediction efficiencies were evaluated by area under curve (AUC) and C-index. Meanwhile, ceRNA regulatory network was constructed by using signature mRNAs, lncRNAs and miRNAs. Results We identified 562 DERs including 42 lncRNAs, 36 miRNAs, and 484 mRNAs. PS prediction model, consisting of 17 optimum prognostic signature DERs, showed that high risk group had significantly poorer prognosis (5-year AUC = 0.951, C-index = 0.788), which also validated in GSE29623. Prognosis prediction model incorporating multi-RNAs with pathologic distant metastasis (M) and pathologic primary tumor (T) (5-year AUC = 0.969, C-index = 0.812) had better efficiency than clinical prognosis prediction model (5-year AUC = 0.712, C-index = 0.680). In the constructed ceRNA regulatory network, lncRNA NCBP2-AS1 could interact with hsa-miR-34c and hsa-miR-363, and lncRNA LINC00115 could interact with hsa-miR-363 and hsa-miR-4709. SIX4, GRAP, NKAIN4, MMAA, and ERVMER34–1 are regulated by hsa-miR-4709. Conclusion Prognosis prediction model incorporating multi-RNAs with pathologic M and pathologic T may have great value in COAD prognosis prediction.

Le génome humain contient environ 8% de séquences rétrovirales endogènes, vestiges d'infections des cellules de la lignée germinale par des rétrovirus infectieux exogènes chez des mammifères ancestraux. La protéine d'enveloppe rétrovirale endogène HEMO (Human Endogenous MER34 ORF), récemment identifiée au laboratoire, provient d'une intégration rétrovirale survenue il y a 100 millions d'années et a été sélectionnée pour une fonction physiologique. Le gène HEMO est exprimé dans les cellules souches, le placenta ainsi que dans un grand nombre de tumeurs. Contrairement aux enveloppes rétrovirales classiques, la protéine HEMO a perdu ses propriétés de fusion, conservées par exemple dans le cas des syncytines. Elle a acquis la propriété remarquable d'être clivée spécifiquement à la membrane de la cellule, puis libérée sous une forme soluble, dite « SHED », dans le milieu extracellulaire. En conséquence, cette forme est présente dans le sang périphérique des femmes enceintes, avec des concentrations qui augmentent tout au long de la grossesse. La protéine HEMO pourrait jouer un rôle dans la physiologie placentaire et/ou exercer une action à distance sur des organes cibles de la femme enceinte. Pour déterminer le rôle de la protéine HEMO dans l'organisme, nous avons cherché ses partenaires membranaires ou récepteurs cellulaires et pour cela, nous avons criblé une banque d'expression en utilisant une méthode innovante de fusion cellule-cellule, qui exploite les propriétés fusogéniques des glycoprotéines H et F du virus de la rougeole. Nous avons alors identifié une interaction spécifique avec une protéase transmembranaire et grâce à des approches de reconstruction de séquences ancestrales, nous avons pu suggérer que cette interaction a été acquise suite à deux mutations, apparues entre 45 et 30 millions d'années chez des ancêtres primates, et qui ont provoquée des modifications structurelles de la protéine HEMO, notamment la perte de son site de clivage à la furine. Cette récente acquisition dans son histoire évolutive pourrait être à l'origine d'une nouvelle fonction. Aussi, nous avons développé un modèle transgénique murin en introduisant le gène HEMO, perdu chez la souris, afin d'identifier l'apparition d'éventuels phénotypes. Enfin, la protéine HEMO constituant une cible thérapeutique potentielle pour traiter certains cancers, nous avons entrepris de développer un anticorps couplé à un agent cytotoxique (Antibody-Drug Conjugate, ADC), pour cibler spécifiquement les tumeurs HEMO positives
The human genome contains approximately 8% endogenous retroviral sequences, which are remnants of infections of germline cells by exogenous infectious retroviruses in ancestral mammals. The endogenous retroviral envelope protein HEMO (Human Endogenous MER34 ORF), recently identified in the laboratory, originates from a retroviral integration that occurred 100 million years ago and has been selected for a physiological function. The HEMO gene is expressed in stem cells, the placenta, and many tumors. Unlike classical retroviral envelopes, the HEMO protein has lost its fusion properties, which are retained, for example, in the case of syncytins. It has acquired the remarkable property to be specifically cleaved at the cell membrane and then released as a “SHED” soluble form, into the extracellular environment. Consequently, the SHED HEMO protein is present in the peripheral blood of pregnant women, with concentrations increasing throughout pregnancy. The HEMO protein could play a role in placental physiology and/or exert effects on distant target organs in pregnant women. To determine the role of the HEMO protein in the organism, we looked for its membrane partners or cellular receptors and screened an expression library using an innovative cell-cell fusion method that leverages the fusogenic properties of the H and F envelope glycoproteins from the measles virus. We then identified a specific interaction with a transmembrane protease, and through ancestral sequence reconstruction approaches, we could suggest that this interaction was acquired following two mutations, which appeared between 45 and 30 million years ago in primate ancestors. These mutations induced structural changes in the HEMO protein, notably by the loss of its furin cleavage site. This recent acquisition in its evolutionary history could be at the origine of a new function. We have therefore developed a murine transgenic model by introducing the HEMO gene, which is absent in mice, in order to identify the appearance of any phenotypes. Finally, since the HEMO protein is a potential therapeutic target for certain cancers, we are developing an antibody-drug conjugate to specifically target HEMO-positive tumors