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  • 1. Apcher, Sebastien
    et al.
    Martins, Rodrigo Prado
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Equipe Labellisée la Ligue Contre le Cancer, Inserm UMR1162, Université Paris, France ; RECAMO, Masaryk Memorial Cancer Institute, Czech Republic.
    The source of MHC class I presented peptides and its implications2016In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 40, p. 117-122Article, review/survey (Refereed)
    Abstract [en]

    The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-todate account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

  • 2.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010 Paris, France.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences/ENT, Uppsala University, 752 36 Uppsala, Sweden.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 12, p. 19389-19402Article in journal (Refereed)
    Abstract [en]

    Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.

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  • 3.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Troiano, Giuseppe
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103437-103448Article in journal (Refereed)
    Abstract [en]

    Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up-regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties.

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  • 4. Fusee, Leila T. S.
    et al.
    Marin, Monica
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lopez, Ignacio
    Alternative Mechanisms of p53 Action During the Unfolded Protein Response2020In: Cancers, ISSN 2072-6694, Vol. 12, no 2, article id 401Article in journal (Refereed)
    Abstract [en]

    The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, Delta 40p53, p53 Delta N40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.

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  • 5. Gnanasundram, Sivakumar Vadivel
    et al.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Translation Stress Regulates Ribosome Synthesis and Cell Proliferation2018In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 12, article id 3757Article, review/survey (Refereed)
    Abstract [en]

    Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3K delta-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

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  • 6. Gnanasundram, Sivakumar Vadivel
    et al.
    Pyndiah, Slovenie
    Daskalogianni, Chrysoula
    Armfield, Kate
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilson, Joanna B.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
    PI3Kδ delta activates E2F1 synthesis in response to mRNA translation stress2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2103Article in journal (Refereed)
    Abstract [en]

    The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein–Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress–response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

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  • 7.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gärskog, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 32579Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

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  • 8.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University Paris 7, St. Louis Hospital, Paris, France .
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High immune cytolytic activity in tumor-free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue2019In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 5, no 4, p. 240-247Article in journal (Refereed)
    Abstract [en]

    Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.

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  • 9.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Krejci, Adam
    Hupp, Ted
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University Paris 7, St. Louis Hospital, Paris, France.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue2019In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 48, no 1, p. 24-30Article in journal (Refereed)
    Abstract [en]

    Background The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment. Materials and methods To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (<= 40 years) and five elderly patients (>= 50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes. Results In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044). Conclusions Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

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  • 10.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; Équipe Labellisée Ligue Contre le Cancer, INSERM UMRS1162, Institut de Génétique Moléculaire, Université Paris 7, IUH Hôpital St. Louis, 75010 Paris, France.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck2019In: Cancers, ISSN 2072-6694, Vol. 11, no 3, article id 347Article in journal (Refereed)
    Abstract [en]

    A growing number of long non-coding RNAs (lncRNAs) have been linked to squamous cell carcinoma of the head and neck (SCCHN). A subclass of lncRNAs, termed enhancer RNAs (eRNAs), are derived from enhancer regions and could contribute to enhancer function. In this study, we developed an integrated data analysis approach to identify key eRNAs in SCCHN. Tissue-specific enhancer-derived RNAs and their regulated genes previously predicted using the computational pipeline PreSTIGE, were considered as putative eRNA-target pairs. The interactive web servers, TANRIC (the Atlas of Noncoding RNAs in Cancer) and cBioPortal, were used to explore the RNA levels and clinical data from the Cancer Genome Atlas (TCGA) project. Requiring that key eRNAs should show significant associations with overall survival (Kaplan-Meier log-rank test, p < 0.05) and the predicted target (correlation coefficient r > 0.4, p < 0.001), we identified five key eRNA candidates. The most significant survival-associated eRNA was AP001056.1 with ICOSLG encoding an immune checkpoint protein as its regulated target. Another 1640 genes also showed significant correlation with AP001056.1 (r > 0.4, p < 0.001), with the "immune system process" being the most significantly enriched biological process (adjusted p < 0.001). Our results suggest that AP001056.1 is a key immune-related eRNA in SCCHN with a positive impact on clinical outcome.

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  • 11. Haronikova, Lucia
    et al.
    Olivares-Illana, Vanesa
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karakostis, Konstantinos
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 4Inserm U1162, Paris, France; ICCVS, University of Gdansk, Science, Gdansk, Poland.
    The p53 mRNA: an integral part of the cellular stress response2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 7, p. 3257-3271Article in journal (Refereed)
    Abstract [en]

    A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

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  • 12. Karakostis, Konstantinos
    et al.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Université Paris 7, INSERM UMR 1131, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic..
    Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, no 1, article id 915Article, review/survey (Refereed)
    Abstract [en]

    Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.

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  • 13. Karakostis, Konstantinos
    et al.
    Gnanasundram, Sivakumar Vadivel
    Lopez, Ignacio
    Thermou, Aikaterini
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olivares-Illana, Vanesa
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. 1 E´quipe Labellise´e Ligue Contre le Cancer, Universite´ Paris 7, 27 Rue Juliette Dodu, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, Czech Republic.
    A single synonymous mutation determines the phosphorylation and stability of the nascent protein2019In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 11, no 3, p. 187-199Article in journal (Refereed)
    Abstract [en]

    p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

  • 14. Karakostis, Konstantinos
    et al.
    Ponnuswamy, Anand
    Fusee, Leila T. S.
    Bailly, Xavier
    Laguerre, Laurent
    Worall, Erin
    Vojtesek, Borek
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. E´quipe Labellise´e Ligue Contre le Cancer, Universite´ Paris 7, INSERM UMR 1162, Paris, France; Regional Centre for Applied Molecular Oncology, RECAMO and Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    p53 mRNA and p53 Protein Structures Have Evolved Independently to Interact with MDM22016In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 33, no 5, p. 1280-1292Article in journal (Refereed)
    Abstract [en]

    The p53 tumor suppressor and its key regulator MDM2 play essential roles in development, ageing, cancer, and cellular stress responses in mammals. Following DNA damage, MDM2 interacts with p53 mRNA in an ATM kinase-dependent fashion and stimulates p53 synthesis, whereas under normal conditions, MDM2 targets the p53 protein for degradation. The peptide-and RNA motifs that interact with MDM2 are encoded by the same conserved BOX-I sequence, but how these interactions have evolved is unknown. Here, we show that a temperature-sensitive structure in the invertebrate Ciona intestinalis (Ci) p53 mRNA controls its interaction with MDM2. We also show that a nonconserved flanking region of Ci-BOX-I domain prevents the p53-MDM2 protein-protein interaction. These results indicate that the temperature-regulated p53 mRNA-MDM2 interaction evolved to become kinase regulated in the mammalian DNA damage response. The data also suggest that the negative regulation of p53 by MDM2 via protein-protein interaction evolved in vertebrates following changes in the BOX-I flanking sequence.

  • 15. Lopez, Ignacio
    et al.
    Tournillon, Anne-Sophie
    Martins, Rodrigo Prado
    Karakostis, Konstantinos
    Malbert-Colas, Laurence
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162 ‘Génomique Fonctionnelle des Tumeurs Solides’, Paris, France ; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress2017In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 24, no 10, p. 1717-1729Article in journal (Refereed)
    Abstract [en]

    Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6. PERK promotes G2 cell cycle arrest and cellular repair by inducing the alternative translated p53 isoform p53.N40 (p53/47), which activates 14-3-3 sigma via suppression of p21(CDKN1A). Here we show that prolonged ER stress promotes apoptosis via a p53-dependent inhibition of BiP expression. This leads to the release of the pro-apoptotic BH3-only BIK from BiP and activation of apoptosis. Suppression of bip mRNA translation is mediated via the specific binding of p53 to the first 346-nt of the bip mRNA and via a p53 trans-suppression domain located within the first seven N-terminal amino acids of p53 Delta N40. This work shows how p53 targets BiP to promote apoptosis during severe ER stress and further illustrates how regulation of mRNA translation has a key role in p53-mediated regulation of gene expression during the UPR.

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  • 16. Lopez, Ignacio
    et al.
    Tournillon, Anne-Sophie
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Univ Paris 07, Equipe Labellisee Ligue Canc, Paris, France; INSERM, UMR Genom Fonct Tumeurs Solides 1162, Paris, France; Masaryk Mem Canc Inst, RECAMO, Brno, Czech Republic.
    p53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress2015In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 21, p. 3373-3378Article in journal (Refereed)
    Abstract [en]

    p53 is activated by different stress and damage pathways and regulates cell biological responses including cell cycle arrest, repair pathways, apoptosis and senescence. Following DNA damage, the levels of p53 increase and via binding to target gene promoters, p53 induces expression of multiple genes including p21(CDKN1A) and mdm2. The effects of p53 on gene expression during the DNA damage response are well mimicked by overexpressing p53 under normal conditions. However, stress to the Endoplasmic Reticulum (ER) and the consequent Unfolded Protein Response (UPR) leads to the induction of the p53/47 isoform that lacks the first 40 aa of p53 and to an active suppression of p21(CDKN1A) transcription and mRNA translation. We now show that during ER stress p53 also suppresses MDM2 protein levels via a similar mechanism. These observations not only raise questions about the physiological role of MDM2 during ER stress but it also reveals a new facet of p53 as a repressor toward 2 of its major target genes during the UPR. As suppression of p21(CDKN1A) and MDM2 protein synthesis is mediated via their coding sequences, it raises the possibility that p53 controls mRNA translation via a common mechanism that might play an important role in how p53 regulates gene expression during the UPR, as compared to the transcription-dependent gene regulation taking place during the DNA damage response.

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  • 17. Martins, Rodrigo Prado
    et al.
    Findakly, Sarah
    Daskalogianni, Chrysoula
    Teulade-Fichou, Marie-Paule
    Blondel, Marc
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Université Paris 7, Inserm, UMR 1162, 75013 Paris, France; ICCVS, University of Gda ´nsk, Science, ul. Wita Stwosza 63, 80-308 Gda ´nsk, Poland; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653 Brno, Czech Republic.
    In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 12, article id 3124Article in journal (Refereed)
    Abstract [en]

    Protein-RNA interactions (PRIs) control pivotal steps in RNA biogenesis, regulate multiple physiological and pathological cellular networks, and are emerging as important drug targets. However, targeting of specific protein-RNA interactions for therapeutic developments is still poorly advanced. Studies and manipulation of these interactions are technically challenging and in vitro drug screening assays are often hampered due to the complexity of RNA structures. The binding of nucleolin (NCL) to a G-quadruplex (G4) structure in the messenger RNA (mRNA) of the Epstein-Barr virus (EBV)-encoded EBNA1 has emerged as an interesting therapeutic target to interfere with immune evasion of EBV-associated cancers. Using the NCL-EBNA1 mRNA interaction as a model, we describe a quantitative proximity ligation assay (PLA)-based in cellulo approach to determine the structure activity relationship of small chemical G4 ligands. Our results show how different G4 ligands have different effects on NCL binding to G4 of the EBNA1 mRNA and highlight the importance of in-cellulo screening assays for targeting RNA structure-dependent interactions.

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  • 18. Martins, Rodrigo Prado
    et al.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Équipe Labellisée Ligue Contre le Cancer, Université Paris 7, INSERM UMR 1162, 27 rue Juliette Dodu, 75010 Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    A matter of maturity: the impact of pre-mRNA processing in gene expression and antigen presentation2017In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 91, p. 203-211Article, review/survey (Refereed)
    Abstract [en]

    RNA processing plays a pivotal role in the diversification of high eukaryotes transcriptome and proteome. The expression of gene products controlling a variety of cellular and physiological processes depends largely on a complex maturation process undergone by pre-mRNAs to become translation-competent mRNAs. Here we review the different mechanisms involved in the pre-mRNA processing and disclose their impact in the gene regulation process in eukaryotic cells. We describe some viral strategies targeting pre-mRNA processing to control gene expression and host immune response and discuss their relevance as tools for a better understanding of cell biology. Finally, we highlight accumulating evidences toward the occurrence of a translation event coupled to mRNA biogenesis in the nuclear compartment and argue how this is relevant for the production of antigenic peptide substrates for the major histocompatibility complex class I pathway.

  • 19. Martins, Rodrigo Prado
    et al.
    Malbert-Colas, Laurence
    Lista, Maria Jose
    Daskalogianni, Chrysoula
    Apcher, Sebastien
    Pla, Marika
    Findakly, Sarah
    Blondel, Marc
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Universite Paris 7, Paris, France; ICCVS, University of Gdansk, Science, Gdansk, Poland; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Nuclear processing of nascent transcripts determines synthesis of full-length proteins and antigenic peptides2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 6, p. 3086-3100Article in journal (Refereed)
    Abstract [en]

    Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.

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  • 20.
    Sgaramella, Nicola
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Medical, Surgical and Dental Specialties, Second University of Naples, Multidisciplinary Naples, Italy; Department of Neuroscience Reproductive and Dentistry Sciences, University of Naples Federico II, Naples, Italy.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; University Paris Diderot, INSERM UMRS1162, Paris, France.
    Califano, Luigi
    Tartaro, Gianpaolo
    Colella, Giuseppe
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Strom, Adrian
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lo Muzio, Lorenzo
    Orabona, Giovanni Dell'Aversana
    Santagata, Mario
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rossiello, Riccardo
    Danielsson, Karin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Strindlund, Klas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lillqvist, Sandra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue2018In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 18, no 3, p. 214-218Article, review/survey (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck, SCCHN, is a heterogeneous group of tumours not only concerning the site of origin but also regarding aetiology. The 5-year survival for the whole group of SCCHN tumours has not significantly improved over the last 20-25 years. Apart from tumour spread to lymph nodes, N status, gains and losses of specific chromosomes are the only factors shown to be independent prognostic markers for these tumours. Worldwide, an increasing number of people ≤ 40 years are seen being affected by tongue SCC, the most common tumour within the SCCHN group. Even without any clinical signs of metastasis, up to 30% of all tongue SCC have histologically detectable spread to lymph nodes. In this mini review, field cancerization, tumour microenvironment, the so called EMT (epithelial mesenchymal transition) process and the role of viruses in development of SCCHN are discussed as well as potential new therapeutic targets. For the group of tongue SCC, with the increasing incidence seen in young patients and particularly women, new data with impact on prognosis and treatment are urgently needed. But as long as data from the analyses of several sub sites are presented as valid for the whole group of tumours, this vital point is missed.

  • 21.
    Sgaramella, Nicola
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Second University of Naples, Multidisciplinary Department of Medical, Surgical and Dental Specialties, Naples, Italy; Department of Neuroscience Reproductive and Dentistry Sciences, University of Naples Federico II, Naples, Italy.
    Lindell Jonsson, Eva
    Uppsala university.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Califano, Luigi
    University of Naples, Italy.
    Coates, Philip J
    University of Dundee, UK.
    Tartaro, Gianpaolo
    Second University of Naples, Italy.
    Lo Muzio, Lorenzo
    University of Foggia, Italy.
    Fåhraeus, Robin
    University Paris Diderot, INSERM UMRS1162, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Colella, Giuseppe
    Second University of Naples, Italy.
    Dell'Aversana Orabona, Giovanni
    University of Naples, Italy.
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Santagata, Mario
    Second University of Naples, Italy.
    Rossiello, Riccardo
    Seconda Universita’ Degli Studi di Napoli, Italy.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Danielsson, Karin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients ≤ 40 years but does not correlate with tumour spread2016In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p 50.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies.

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  • 22.
    Sgaramella, Nicola
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Multidisciplinary Department of Medical, Surgical and Dental Specialties, Second University of Naples; 3 Department of Neuroscience Reproductive and Dentistry Sciences, University of Naples Federico II, I-801 38 Naples, Italy.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Hassellöf, Petra
    Califano, Luigi
    Lo Muzio, Lorenzo
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; University Paris Diderot, INSERM UMRS1162, Paris 75010, France.
    Spaak, Lena Norberg
    Franco, Renato
    Tartaro, Gianpaolo
    Colella, Giuseppe
    Santagata, Mario
    Orabona, Giovanni Dell'Aversana
    Chirico, Fabrizio
    Danielsson, Karin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Troiano, Giuseppe
    Ardito, Fatima
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue2018In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 16, no 5, p. 6603-6607Article in journal (Refereed)
    Abstract [en]

    The oral tongue is the most common site for tumours within the oral cavity. Despite intense research, there has been no improvement in the survival rate for patients with oral tongue squamous cell carcinoma (OTSCC) during the last decades. Differences between oral cancer patients based on ethno-geographical distribution have been reported. The present study used immunohistochemistry to evaluate commonly used markers of cancer cell phenotypes, E-cadherin, -catenin and cytokeratins 5 and 19, in 120 patients with OTSCC. To evaluate the impact of ethnicity, patients from Sweden and Italy were included. A higher proportion of Swedish patients exhibited high expression of E-cadherin in their tumours (P=0.039), and high levels of E-cadherin in Swedish OTSCC patients that had succumbed to their disease were associated with poor prognosis. These data demonstrated differences in the pathological characteristics of OTSCC between two different European populations. The findings emphasise the need to take ethnicity/geographical location of patients into account when comparing results from different studies of OTSCC.

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  • 23.
    Strindlund, Klas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Troiano, Giuseppe
    Sgaramella, Nicola
    Coates, Philip J.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Califano, Luigi
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Hôpital St. Louis, Université Paris 7, Paris, France.
    Muzio, Lorenzo Lo
    Ardito, Fatima
    Colella, Giuseppe
    Tartaro, Gianpaolo
    Franco, Renato
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Saadat, Mohammad
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Patients with high c-MYC-expressing squamous cell carcinomas of the tongue show better survival than those with low- and medium-expressing tumours2017In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 46, no 10, p. 967-971Article in journal (Refereed)
    Abstract [en]

    Backgroundc-MYC is a potent oncoprotein with roles in a wide range of cellular processes such as differentiation, apoptosis and growth control. Deregulation of the MYC gene is commonly seen in human tumours resulting in overexpression of the protein. Here we studied expression of c-MYC in correlation to clinical outcome in patients with primary squamous cell carcinoma of the mobile tongue. MethodsImmunohistochemistry was used to identify c-MYC in a group of 104 tongue squamous cell carcinomas with an antibody directed against the N-terminal part of the protein. Staining was evaluated by multiplying the percentage of c-MYC-expressing cells with staining intensity, giving a quick score for each tumour. ResultsAll 104 tumours expressed c-MYC at varying levels. Quantitation according to per cent of positive cells and staining intensity revealed that most (15/21; 71%) high-expressing tumours were seen in males. Within the group of high c-MYC-expressing tumours, the majority were alive 2 and 5 years after treatment. ConclusionsThe present findings show that expression of c-MYC has prognostic value in squamous cell carcinoma of the tongue, and could be useful in choice of therapy.

  • 24. Tournillon, A-S
    et al.
    Lopez, I.
    Malbert-Colas, L.
    Findakly, S.
    Naski, N.
    Olivares-Illana, V.
    Karakostis, K.
    Vojtesek, B.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Equipe Labellisée la Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St Louis, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    p53 binds the mdmx mRNA and controls its translation2017In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 5, p. 723-730Article in journal (Refereed)
    Abstract [en]

    MDMX and MDM2 are two nonredundant essential regulators of p53 tumor suppressor activity. MDM2 controls p53 expression levels, whereas MDMX is predominantly a negative regulator of p53 trans-activity. The feedback loops between MDM2 and p53 are well studied and involve both negative and positive regulation on transcriptional, translational and post-translational levels but little is known on the regulatory pathways between p53 and MDMX. Here we show that overexpression of p53 suppresses mdmx mRNA translation in vitro and in cell-based assays. The core domain of p53 binds the 5' untranslated region (UTR) of the mdmx mRNA in a zinc-dependent manner that together with a trans-suppression domain located in p53 N-terminus controls MDMX synthesis. This interaction can be visualized in the nuclear and cytoplasmic compartment. Fusion of the mdmx 5' UTR to the ovalbumin open reading frame leads to suppression of ovalbumin synthesis. Interestingly, the transcription inactive p53 mutant R273H has a different RNA-binding profile compared with the wild-type p53 and differentiates the synthesis of MDMX isoforms. This study describes p53 as a trans-suppressor of the mdmx mRNA and adds a further level to the intricate feedback system that exist between p53 and its key regulatory factors and emphasizes the important role of mRNA translation control in regulating protein expression in the p53 pathway.

  • 25. Uhrik, Lukas
    et al.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haronikova, Lucia
    Medina-Medina, Ixaura
    Rebolloso-Gomez, Yolanda
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vojtesek, Borivoj
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hernychova, Lenka
    Olivares-Illana, Vanesa
    Allosteric changes in HDM2 by the ATM phosphomimetic S395D mutation: implications on HDM2 function2019In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 476, p. 3401-3411Article in journal (Refereed)
    Abstract [en]

    Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ataxia telangiectasia mutated kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2-p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

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  • 26. Urban-Wojciuk, Zuzanna
    et al.
    Khan, Mohd M.
    Oyler, Benjamin L.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. International Centre for Cancer Vaccine Science (ICCVS), University of Gdansk, Gdansk, Poland; Université Paris 7, INSERM, UMR 1162, Paris, France; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia.
    Marek-Trzonkowska, Natalia
    Nita-Lazar, Aleksandra
    Hupp, Ted R.
    Goodlett, David R.
    The Role of TLRs in Anti-cancer Immunity and Tumor Rejection2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2388Article, review/survey (Refereed)
    Abstract [en]

    In recent years, a lot of scientific interest has focused on cancer immunotherapy. Although chronic inflammation has been described as one of the hallmarks of cancer, acute inflammation can actually trigger the immune system to fight diseases, including cancer. Toll-like receptor (TLR) ligands have long been used as adjuvants for traditional vaccines and it seems they may also play a role enhancing efficiency of tumor immunotherapy. The aim of this perspective is to discuss the effects of TLR stimulation in cancer, expression of various TLRs in different types of tumors, and finally the role of TLRs in anti-cancer immunity and tumor rejection.

  • 27.
    Wilms, Torben
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Khan, Gulfaraz
    Coates, Philip J
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno, Czech Republic; Univ Paris Diderot, INSERM, UMRS1162, 27 Rue Juliette Dodu, Paris, France .
    Hassani, Asma
    Philip, Pretty S
    Norberg Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Califano, Luigi
    Colella, Giuseppe
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Franco, Renato
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    No evidence for the presence of Epstein-Barr virus in squamous cell carcinoma of the mobile tongue2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184201Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases.

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  • 28. Yewdell, Jonathan W.
    et al.
    Dersh, Devin
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm, Paris, France; International Centre for Cancer Vaccine Science (ICCVS), University of Gdansk, Science, Gdansk, Poland; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Peptide Channeling: The Key to MHC Class I Immunosurveillance?2019In: Trends in Cell Biolology, ISSN 0962-8924, E-ISSN 1879-3088, Vol. 29, no 12, p. 929-939Article, review/survey (Refereed)
    Abstract [en]

    MHC class I presentation of short peptides enables CD8(+) T cell (TCD8+) immunosurveillance of tumors and intracellular pathogens. A key feature of the class I pathway is that the immunopeptidome is highly skewed from the cellular degradome, indicating high selectivity of the access of protease-generated peptides to class I molecules. Similarly, in professional antigen-presenting cells, peptides from minute amounts of proteins introduced into the cytosol outcompete an overwhelming supply of constitutively generated peptides. Here, we propose that antigen processing is based on substrate channeling and review recent studies from the antigen processing and cell biology fields that provide a starting point for testing this hypothesis.

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