Vassilis G Gorgoulis

The University of Manchester, Manchester, England, United Kingdom

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Publications (242)1327.15 Total impact

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    Full-text · Dataset · Feb 2016
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    ABSTRACT: Factors linking inflammation and cancer are of great interest. We now report that the chromatin-targeting E3 ubiquitin ligase RNF20/RNF40, driving histone H2B monoubiquitylation (H2Bub1), modulates inflammation and inflammation-associated cancer in mice and humans. Downregulation of RNF20 and H2Bub1 favors recruitment of p65-containing nuclear factor κB (NF-κB) dimers over repressive p50 homodimers and decreases the heterochromatin mark H3K9me3 on a subset of NF-κB target genes to augment their transcription. Concordantly, RNF20+/− mice are predisposed to acute and chronic colonic inflammation and inflammation-associated colorectal cancer, with excessive myeloid-derived suppressor cells (MDSCs) that may quench antitumoral T cell activity. Notably, colons of human ulcerative colitis patients, as well as colorectal tumors, reveal downregulation of RNF20/RNF40 and H2Bub1 in both epithelium and stroma, supporting the clinical relevance of our tissue culture and mouse model findings.
    No preview · Article · Feb 2016 · Cell Reports
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    ABSTRACT: Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCFCyclin F ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCFCyclin F-mediated mechanism required for precise once per cell cycle replication.
    Full-text · Article · Jan 2016 · Nature Communications
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    ABSTRACT: Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.
    No preview · Article · Dec 2015 · Seminars in Cancer Biology
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: Research interest on abdominal aorta branches and abdominal viscera morphometry is renewed by technologic evolution and development of new radiologic and clinical applications including grafted stents and chemoembolization materials. Despite that, data on morphometry of abdominal aorta branches and abdominal viscera are lacking. To investigate this subject authors performed a morphometric study on 50 adult fresh and embalmed Caucasian cadavers and examined abdominal aorta branches', kidney's and spleen's morphometry. Our results on arteries' morphometry did not differ significantly from those of the literature yet we discovered significant differences between fresh and embalmed cadavers on viscera morphometry, spleen and kidneys. We also found previously unreported correlations between abdominal aorta branches' morphometric characteristics. Even more we identified correlations between regional arteries and viscera morphometric characteristics, proposing a new factor determining viscera development. Finally we performed an extensive literature review so to place our results in an anatomic, embryologic and even more a clinical context. We believe that our results add knowledge on abdominal aorta branches and viscera morphometry and are valuable for clinical, radiological and surgical applications including visceral arteries' aneurysms investigation and treatment, chemoembolization procedures, grafted stents design and transplantation.
    No preview · Article · Sep 2015 · Folia morphologica
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    ABSTRACT: MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2015 · Molecular Carcinogenesis
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    ABSTRACT: Cardiovascular diseases (CVDs) have become a predominant cause of death worldwide. Although CVDs encompass a variety of pathological conditions that affect the heart and blood vasculature, they can be classified into two major groups according to their basic pathophysiologic mechanisms, namely atherosclerosis and aneurysm formation. Increasing evidence implicates micro-RNAs (miRNAs or miRs) as vital factors both in the initiation and progression processes of CVDs. Some miRs have a promoting role in CVD development, while others have a protective role. Today, miRs have been shown to be potential biomarkers for several types of CVDs, while strategies targeting miRs are under consideration as potential tools for exploitation in therapeutic approaches for CVD treatments. In this review, we present the available data on the involvement of miRs in CVDs, focusing on their role as regulators of the inflammatory process as an initiating and driving component of CVDs.
    No preview · Article · Jul 2015 · Current Medicinal Chemistry
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    ABSTRACT: The characteristic feature of healthy living organisms is the preservation of homeostasis. Compelling evidence highlight that the DNA damage response and repair (DDR/R) and immune response (ImmR) signaling networks work together favoring the harmonized function of (multi)cellular organisms. DNA and RNA viruses activate the DDR/R machinery in the host cells both directly and indirectly. Activation of DDR/R in turn favors the immunogenicity of the incipient cell. Hence, stimulation of DDR/R by exogenous or endogenous insults triggers innate and adaptive ImmR. The immunogenic properties of ionizing radiation, a prototypic DDR/R inducer, serve as suitable examples of how DDR/R stimulation alerts host immunity. Thus, critical cellular danger signals stimulate defense at the systemic level and vice versa. Disruption of DDR/R-ImmR cross talk compromises (multi)cellular integrity, leading to cell-cycle-related and immune defects. The emerging DDR/R-ImmR concept opens up a new avenue of therapeutic options, recalling the Hippocrates quote "everything in excess is opposed by nature." Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Pharmacology [?] Therapeutics
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    ABSTRACT: Breast cancers are the most common cancer-affecting women; critically the identification of novel biomarkers for improving early detection, stratification and differentiation from benign tumours is important for the reduction of morbidity and mortality.To identify and functionally characterise potential biomarkers, we used mass spectrometry (MS) to analyse serum samples representing control, benign breast disease (BBD) and invasive breast cancer (IDC) patients. Complementary and multidimensional proteomic approaches were used to identify and validate novel serum markers.Annexin A3 (ANX A3) was found to be differentially expressed amongst different breast pathologies. The diagnostic value of serum ANX A3 was subsequently validated by ELISA in an independent serum set representing the three groups. Here, ANX A3 was significantly upregulated in the benign disease group sera compared with other groups (P < 0.0005).In addition, paired breast tissue immunostaining confirmed that ANX A3 was abundantly expressed in benign and to a lesser extent malignant neoplastic epithelium. Finally, we illustrated ANX A3 expression in cell culture lysates and conditioned media from neoplastic breast cell lines, and its role in neoplastic breast cell migration in vitro.This study confirms the novel role of ANX A3 as a mammary biomarker, regulator and therapeutic target.
    Full-text · Article · Jun 2015 · Oncotarget
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    ABSTRACT: IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and anti-tumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15−/- and Il15rα−/- mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15−/- but not Il15rα−/- mice showed reduced survival, along with higher tumor incidence, colon weight and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15−/- mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFN-γ, G-CSF, IL-10 and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. Whilst these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that loss of IL-15 up-regulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5 and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of anti-tumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.
    No preview · Article · May 2015 · OncoImmunology
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    ABSTRACT: Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.
    Full-text · Article · Apr 2015 · Oncotarget
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    ABSTRACT: Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Cell Reports
  • L Golomb · A Sagiv · I S Pateras · A Maly · V Krizhanovsky · V G Gorgoulis · M Oren · A Ben-Yehuda
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    ABSTRACT: Aging is the single biggest risk factor for malignant transformation. Among the most common age-associated malignancies are non-melanoma skin cancers, comprising the most common types of human cancer. Here we show that mutant H-Ras activation in mouse epidermis, a frequent event in cutaneous squamous cell carcinoma (SCC), elicits a differential outcome in aged versus young mice. Whereas H-Ras activation in the young skin results in hyperplasia that is mainly accompanied by rapid hair growth, H-Ras activation in the aged skin results in more dysplasia and gradual progression to in situ SCC. Progression is associated with increased inflammation, pronounced accumulation of immune cells including T cells, macrophages and mast cells as well as excessive cell senescence. We found not only an age-dependent increase in expression of several pro-inflammatory mediators, but also activation of a strong anti-inflammatory response involving enhanced IL4/IL10 expression and immune skewing toward a Th2 response. In addition, we observed an age-dependent increase in the expression of Pdl1, encoding an immune suppressive ligand that promotes cancer immune evasion. Moreover, upon switching off oncogenic H-Ras activity, young but not aged skin regenerates successfully, suggesting a failure of the aged epidermal stem cells to repair damaged tissue. Our findings support an age-dependent link between accumulation of senescent cells, immune infiltration and cancer progression, which may contribute to the increased cancer risk associated with old age.
    No preview · Article · Mar 2015 · Cell Death and Differentiation
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    ABSTRACT: IGF-1 is one of the key molecules in cancer biology; however, little is known about the role of the preferential expression of the premature IGF-1 isoforms in prostate cancer. We have examined the role of the cleaved COO(-) terminal peptide (PEc) of the third IGF-1 isoform, IGF-1Ec, in prostate cancer. Our evidence suggests that endogenously produced PEc induces cellular proliferation in the human prostate cancer cells (PC-3) in-vitro and in-vivo, by activating the ERK 1/2 pathway in an autocrine/paracrine manner. PEc overexpressing cells and tumors presented evidence of epithelial to mesenchymal transition, whereas the orthotopic injection of PEc overexpressing, normal prostate epithelium cells (HPrEC) in SCID mice was associated with increased metastatic rate. In humans, the IGF-1Ec expression was detected in prostate cancer biopsies, where its expression correlates with tumor stage. Our data underlies the action of PEc in prostate cancer biology and defines its potential role in tumor growth, progression and metastasis.
    No preview · Article · Jan 2015 · Molecular Medicine
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    ABSTRACT: Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.
    Full-text · Article · Sep 2014 · Cellular and Molecular Life Sciences CMLS
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    ABSTRACT: Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. Other ARF activities, particularly p53-independent ones, that could help in understanding cancer development and provide potential therapeutic exploitation are underrated. Although ARF is generally not expressed in normal tissues, it is essential for ocular and male germ cells development. The underlying mechanism(s) in these processes, while not clearly defined, point toward a functional link between ARF, DNA damage and angiogenesis. Based on a recent study from our group demonstrating a functional interplay between ataxia-telangiectasia mutated (ATM) and ARF during carcinogenesis, we discuss the role of ARF at the crossroads of cancer and developmental processes.
    Full-text · Article · Jul 2014 · Frontiers in Genetics
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    Tomer Cooks · Ioannis S Pateras · Vassilis G Gorgoulis
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    ABSTRACT: Mutant p53 functions as a key molecular element in the inflamed colon tissue joining forces with nuclear factor kappa-B (NF-κB) to prolong and intensify the inflammatory response, leading eventually to a higher risk for colitis associated colorectal cancer (CAC). This phenomenon coincides with the fact that mutations in p53 are an initiating factor of CAC unlike sporadic colorectal cancer (CRC) where they are considered a late event contributing to tumor progression. This research highlight attempts to illuminate the consequences of such a reshuffling in the molecular sequence of events from non-cancerous tissue to invasive carcinoma of the colon. Implications of this different role taken by mutant p53 when inflammation is involved might affect tumorigenesis, pathogenesis, and hierarchical morphogenesis and suggest the reevaluation of current animal models used to study CAC. We also discuss the possible role of mutant p53 in stromal and immune compartments, either in an autonomous or non-autonomous manner. Cancer Cell & Microenvironment 2014; 1:66-71. doi: 10.14800/ccm.135; © 2014 by Smart Science & Technology, LLC. The monolayered epithelia of the intestine have to maintain a constant delicate balance, taking into account radical changes at the luminal end. Throughout this continuous battle, which involves exposure to harsh mechanical, chemical and biological conditions, the intestinal epithelium is required to juggle between the absorption of nutrients and metabolites while restricting the penetration of unwelcome infectious agents [1, 2]
    Full-text · Article · Jul 2014
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    ABSTRACT: Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents. <http://www.nature.com/cdd/journal/vaop/ncurrent/abs/cdd201416a.html>
    Full-text · Article · Jun 2014 · Cell Death and Differentiation

  • No preview · Article · May 2014 · European Journal of Neurology

Publication Stats

9k Citations
1,327.15 Total Impact Points

Institutions

  • 2014-2015
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2011-2015
    • Academy of Athens
      Athínai, Attica, Greece
  • 2006-2015
    • National and Kapodistrian University of Athens
      • • Division of Histology - Embryology
      • • Department of Medicine
      Athínai, Attica, Greece
    • Danish Cancer Society
      København, Capital Region, Denmark
  • 2006-2013
    • Harokopion University of Athens
      Athínai, Attica, Greece
  • 2012
    • Hospital Universitario Madrid Sanchinarro
      Madrid, Madrid, Spain
  • 2009
    • Palacký University of Olomouc
      • Laboratory of Genome Integrity
      Olmütz, Olomoucký, Czech Republic
  • 2007
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2002-2007
    • University of Patras
      • • Department of General Biology
      • • School of Medicine
      Rhion, West Greece, Greece
  • 2005
    • Agricultural University of Athens
      Athínai, Attica, Greece
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2003-2005
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2004
    • Wistar Institute
      Filadelfia, Pennsylvania, United States
  • 1995-2004
    • Laiko Hospital
      • First Department of Surgery
      Athínai, Attica, Greece
  • 2001
    • University of Ioannina
      • School of Medicine
      Yannina, Epirus, Greece
  • 2000-2001
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 1993-1999
    • Red Cross Hospital, Athens
      Athínai, Attica, Greece
    • University Hospital of Heraklion
      Irákleio, Attica, Greece