Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors

Extracellular vesicles (EVs) are important components of the metastatic niche and are crucial in infiltration, metastasis, and immune tolerance processes during tumorigenesis. We hypothesized that human endogenous retroviruses (HERV) positive EVs derived from tumor cellsmay have a role in modulating the innate immune response. The study was conducted in two different colorectal cancer cell lines, representing different stages of cancer development: Caco-2, derived from a non-metastatic colorectal adenocarcinoma, and SK-CO-1, derived from metastatic colorectal adenocarcinoma (ascites). Both cell lines were treated with decitabine to induce global hypomethylation and to reactivate HERV expression. EVs were quantified by nanoparticle tracking analysis, and HERV-positive EV concentrations were measured by flow cytometry. The effect of EVs isolated from both untreated and decitabine-treated cells on the innate immune response was evaluated by injecting them in zebrafish embryos and then assessing Interleukin 1β (IL1-β), Interleukin 10 (IL-10), and the myeloperoxidase (mpx) expression levels by real-time qPCR. Interestingly, HERV-K positive EVs concentrations were significantly associated with a reduced expression of IL1-β and mpx, supporting our hypothesis that HERV-positive EVs may act as immunomodulators in tumor progression. The obtained results open new perspectives about the modulation of the immune response in cancer therapy.

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Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

Cancers ◽

10.3390/cancers12030610 ◽

2020 ◽

Vol 12 (3) ◽

pp. 610 ◽

Cited By ~ 5

Author(s):

Vincent Alcazer ◽

Paola Bonaventura ◽

Stephane Depil

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Endogenous Retroviruses ◽

Interferon Response ◽

Human Endogenous Retroviruses ◽

Dna Production ◽

Potential Impact ◽

Multiple Conditions

Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs are mostly localized in the heterochromatin and silenced by methylation. Multiple conditions have been described to induce their reactivation, including auto-immune diseases and cancers. HERVs re-expression leads to RNA (simple and double-stranded) and DNA production (by reverse transcription), modulating the innate immune response. Some studies also argue for a role of HERVs in shaping the evolution of innate immunity, notably in the development of the interferon response. However, their exact role in the innate immune response, particularly in cancer, remains to be defined. In this review, we see how HERVs could be key-players in mounting an antitumor immune response. After a brief introduction on HERVs characteristics and biology, we review the different mechanisms by which HERVs can interact with the immune system, with a focus on the innate response. We then discuss the potential impact of HERVs expression on the innate immune response in cancer.

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UHRF1 suppresses viral mimicry through both DNA methylation-dependent and -independent mechanisms

10.1101/2020.08.31.274894 ◽

2020 ◽

Author(s):

RE Irwin ◽

CA Scullion ◽

SJ Thursby ◽

ML Sun ◽

A Thakur ◽

...

Keyword(s):

Dna Methylation ◽

Immune Response ◽

Cell Lines ◽

Cancer Cell ◽

Innate Immune Response ◽

Point Mutations ◽

Innate Immune ◽

Lung Fibroblasts ◽

Interferon Response ◽

Viral Mimicry

AbstractSome chemotherapeutic agents which cause loss of DNA methylation have been recently shown to induce a state of “viral mimicry” involving upregulation of endogenous retroviruses (ERV) and a subsequent innate immune response. This approach may be useful in combination with immune checkpoint cancer therapies, but relatively little is known about normal cellular control of ERV suppression. The UHRF1 protein can interact with the maintenance methylation protein DNMT1 and is known to play an important role in epigenetic control in the cell. To examine potential roles of this protein in differentiated cells, we first established stable knockdowns in normal human lung fibroblasts. While these knockdown cells showed the expected loss of DNA methylation genome-wide, transcriptional changes were instead dominated by a single response, namely activation of innate immune signalling, consistent with viral mimicry. We confirmed using mechanistic approaches that activation of interferons and interferon-stimulated genes involved in double-stranded RNA detection was crucial to the response. ERVs were demethylated and transcriptionally activated in UHRF1 knockdown cells. As in these normal cell lines, ERV activation and interferon response also occurred following the transient loss of UHRF1 in both melanoma and colon cancer cell lines. Restoring UHRF1 in either transient- or stable knockdown systems abrogated ERV reactivation and interferon response, but without substantial restoration of DNA methylation. Rescued cell lines were hypersensitive to depletion of SETDB1, implicating H3K9me3 as crucial to UHRF1-mediated repression in the absence of DNA methylation. Confirming this, cells rescued with UHRF1 containing point mutations affecting H3K9me3 binding could not mediate silencing of ERV transcription or the innate immune response. Finally, by introducing similar point mutations in the mouse homologue, we could show that this pathway is conserved in mice. Our results therefore implicate UHRF1 as a key regulator of ERV suppression and strengthen the basis for cancer cell hypomethylation therapy.

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Donor Hepatic Steatosis Induce Exacerbated Ischemia-Reperfusion Injury Through Activation of Innate Immune Response Molecular Pathways

Transplantation Journal ◽

10.1097/tp.0000000000000857 ◽

2015 ◽

Vol 99 (12) ◽

pp. 2523-2533 ◽

Cited By ~ 30

Author(s):

Ricardo C. Gehrau ◽

Valeria R. Mas ◽

Catherine I. Dumur ◽

Jihee L. Suh ◽

Ashish K. Sharma ◽

...

Keyword(s):

Immune Response ◽

Reperfusion Injury ◽

Hepatic Steatosis ◽

Innate Immune Response ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Innate Immune ◽

Molecular Pathways

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Systems Biology to Understand and Regulate Human Retroviral Proinflammatory Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.736349 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohamed Helmy ◽

Kumar Selvarajoo

Keyword(s):

Immune Response ◽

Systems Biology ◽

Transposable Elements ◽

Innate Immune Response ◽

Innate Immune ◽

Endogenous Retroviruses ◽

Therapeutic Approaches ◽

Genome Sequences ◽

Proinflammatory Response ◽

Novel Therapeutic

The majority of human genome are non-coding genes. Recent research have revealed that about half of these genome sequences make up of transposable elements (TEs). A branch of these belong to the endogenous retroviruses (ERVs), which are germline viral infection that occurred over millions of years ago. They are generally harmless as evolutionary mutations have made them unable to produce viral agents and are mostly epigenetically silenced. Nevertheless, ERVs are able to express by still unknown mechanisms and recent evidences have shown links between ERVs and major proinflammatory diseases and cancers. The major challenge is to elucidate a detailed mechanistic understanding between them, so that novel therapeutic approaches can be explored. Here, we provide a brief overview of TEs, human ERVs and their links to microbiome, innate immune response, proinflammatory diseases and cancer. Finally, we recommend the employment of systems biology approaches for future HERV research.

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Aberrant DNA Methylation in Cholangiocarcinoma

10.20944/preprints201705.0127.v1 ◽

2017 ◽

Author(s):

Toshiaki Nakaoka ◽

Yoshimasa Saito ◽

Hidetsugu Saito

Keyword(s):

Dna Methylation ◽

Immune Response ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Ampulla Of Vater ◽

Endogenous Retroviruses ◽

Epigenetic Therapy ◽

Suppressor Genes ◽

Aberrant Dna Methylation ◽

Dna Methylation Inhibitors

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

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Identification of genes and molecular pathways involved in a C. elegans model of neuroborreliosis

Proceedings of IMPRS ◽

10.18060/22747 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Ruben Prado ◽

Gai-Linn Bessing ◽

Nathaniel Snyder ◽

Gurpalik Singh ◽

Frank Yang ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Lyme Disease ◽

Innate Immune Response ◽

Genetic Model ◽

Protein Aggregates ◽

Neuronal Morphology ◽

Innate Immune ◽

Molecular Pathways ◽

C Elegans

Background and Hypothesis: Lyme disease is caused by the spirochaete bacteria from the Borrelia species. Recent studies suggest that Lyme disease may be associated with dementia, brain atrophy, and protein aggregates that may be associated with the development of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimers disease (AD). The molecular basis of the Borrelia-associated innate immune response and associated neuropathology is poorly defined. A significant hindrance in dissecting these molecular components is the lack of facile in vivo genetic models to explore the mechanisms involved in the neuropathology. Here we hypothesize that the nematode C. elegans will be a useful model for Borrelia-associated innate immunity and neuropathology. Project Methods: We utilized transcriptional reporters, transgenic animals, neuronal morphology analysis, RNAi, host defense pathways, AD- and PD-associated pathologies, and behavior assays to determine the effect that Borrelia has on C. elegans viability. Results: C. elegans can be infected and survive using Borrelia as a food source, and the bacteria can induce highly conserved innate immune response pathways, and exacerbate PD-associated dopamine neuronal death in human A53T -synuclein-expressing animals. C. elegans models expressing AD-associated human A 1-42 also show significant movement defects and increased protein aggregates when exposed to Borrelia. Conclusions and Potential Impact: This study further characterizes a novel genetic model for Borrelia-associated innate immunity and neuropathology. Incorporating C. elegans genetic screens, this model should allow us to identify mediators of the Borrelia-associated pathologies that should facilitate the identification of molecular pathways and potential therapeutic targets.

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Activation of the innate immune response by endogenous retroviruses

Journal of General Virology ◽

10.1099/vir.0.000017 ◽

2015 ◽

Vol 96 (Pt_6) ◽

pp. 1207-1218 ◽

Cited By ~ 24

Author(s):

T. P. Hurst ◽

G. Magiorkinis

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Endogenous Retroviruses

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Activation of the innate immune response by endogenous retroviruses

Journal of General Virology ◽

10.1099/jgv.0.000017 ◽

2015 ◽

Vol 96 (6) ◽

pp. 1207-1218 ◽

Cited By ~ 37

Author(s):

Tara P. Hurst ◽

Gkikas Magiorkinis

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Endogenous Retroviruses

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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