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  • 1.
    Attaran, Nima
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip
    Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno 656 53, Czech Republic.
    Zborayova, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Erdogan, Baris
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Magan, Mustafa
    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.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Antigen peptide transporters are upregulated in squamous cell carcinoma of the oral tongue and show sex‑specific associations with survival2022In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 24, no 5, article id 390Article in journal (Refereed)
    Abstract [en]

    Transporter associated with antigen processing 1 (TAP1) and TAP2 serve pivotal roles in adaptive immunity. Tumor cells often show reduced antigen presentation on their surface as one mechanism to escape immune recognition. Whether downregulation of TAPs is a common mechanism of tumor immune evasion in squamous cell carcinoma of the oral tongue (SCCOT) is unclear. In the present study, samples from 78 patients with SCCOT and 17 patients with benign hyperplastic tongue lesions were analyzed for TAP1 and TAP2 expression by immunohistochemistry. The percentage of positive cells and staining intensity were scored. Associations with clinicopathological variables and survival outcome were also investigated. The results demonstrated that TAP1 and TAP2 levels were highly associated with each other in individual samples and were upregulated in SCCOT compared with benign lesions (P<0.001). The proportion of TAP1‐ or TAP2‐positive tumor cells was >80% in all but two of the tumors, whereas 25.6 and 23.0% of the tumors showed weak intensity of TAP1 and TAP2, respectively. There were no significant associations with clinicopathological variables or survival outcomes between TAP‐intermediate/strong and TAP‐weak tumors. However, in patients <70 years old and with early stage SCCOT, male patients had better outcomes than female patients (log‐rank P<0.05), and the best outcome was observed in male patients with intermediate/strong TAP expression. In conclusion, loss of TAP was not a frequent event in SCCOT and stronger TAP expression in male patients was associated with improved survival, providing further evidence for sex‐specific immune modulation in cancer.

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  • 2.
    Attaran, Nima
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gu, Xiaolian
    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.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zborayova, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Downregulation of TAP1 in Tumor-Free Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Indicator of Better Survival.2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 17, article id E6220Article in journal (Refereed)
    Abstract [en]

    Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The results showing that TAP1 levels in tumor-free tongue tissue contralateral to the SCCOT correlate with survival is an important contribution to early diagnosis and follow up of SCCOT.

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  • 3.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Bourdon, Jean-Christophe
    Coates, Philip J
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Expression of p53 isoforms in squamous cell carcinoma of the head and neck.2007In: Eur J Cancer, ISSN 0959-8049, Vol. 43, no 3, p. 617-23Article in journal (Refereed)
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  • 4.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, P J
    Laurell, G
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fahraeus, R
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 11, p. 1760-1765Article in journal (Refereed)
    Abstract [en]

    Background: The overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general. Methods: On the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples. Results: Levels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes. Conclusions: Our patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.

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  • 5.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Regional Centre forApplied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University of Paris St. Louis Hospital, Paris, France.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Baumgarth, Jonathan
    Norberg-Spaak, Lena
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Levels of MUC1 in tumours and serum of patients with different sub-types of squamous cell carcinoma of the head and neck2020In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 20, no 2, p. 1709-1718Article in journal (Refereed)
    Abstract [en]

    Mucin 1 (MUC1) is a membrane-bound and secreted glycoprotein that has a protective role in surface epithelia. We recently demonstrated that MUC1 mRNA expression was upregulated in tumour-free tongue tissues adjacent to squamous cell carcinoma of the oral tongue (SCCOT) compared with that in the tumour tissues. The present study investigated MUC1 protein in SCCOT tissue and serum from patients with squamous cell carcinoma of the head and neck (SCCHN) at different sub-sites. The results from immunohistochemistry demonstrated that all SCCOT tissues expressed MUC1; however, the protein levels were not correlated with MUC1 mRNA levels in the same tumours. Furthermore, serum MUC1 level was lower in patients with SCCOT, tonsil SCC and gingival SCC compared with that in healthy subjects; however, the difference was only significant for patients with SCCOT (P=0.0421). No correlation was seen between MUC1 level in tumour tissues and MUCI level in serum from the same patients. The absence of correlation between MUC1 protein and mRNA levels in SCCOT tissues emphasized the importance of validating genomic data in clinical samples. Although significant MUC1 downregulation was observed in the serum of patients with SCCOT, there was a large variation within the groups, suggesting that MUC1 may not be used as a biomarker for these types of tumors.

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  • 6.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip
    Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University of Paris St. Louis Hospital, Paris, France.
    Wilms, Torben
    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.
    Low potential of circulating interleukin 1 receptor antagonist as a prediction marker for squamous cell carcinoma of the head and neck2021In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 50, no 8, p. 785-794Article in journal (Refereed)
    Abstract [en]

    Background: Circulating markers are attractive molecules for prognosis and management of cancer that allow sequential monitoring of patients during and after treatment. Based on previous protein profiling data, circulating interleukin 1 receptor antagonist (IL-1Ra) was evaluated as a potential diagnostic and prognostic marker for squamous cell carcinomas of the head and neck (SCCHN). In this study, we aimed at confirming the clinical relevance of plasma IL-1Ra in SCCHN and exploring its potential as a prediction marker for SCCHN.

    Methods: Plasma from 87 patients with SCCHN, control plasma from 28 healthy individuals and pre-diagnostic plasma from 44 patients with squamous cell carcinoma of the oral tongue (SCCOT) and 88 matched controls were analysed with IL-1Ra electrochemiluminescence immunoassays from mesoscale diagnostics.

    Results: Plasma IL-1Ra was found to be up-regulated in patients with oral tongue, gingiva and base of tongue tumours compared to healthy individuals (p < 0.01). IL-1Ra levels positively correlated with tumour size (p < 0.01) and body mass index (p = 0.013). Comparing pre-diagnostic plasma to the matched controls, similar IL1-Ra levels were seen (p = 0.05).

    Conclusion: The anti-inflammatory cytokine IL-1Ra could be a diagnostic marker for SCCHN, whereas its potential as a cancer prediction marker was not supported by our data.

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  • 7.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma: identification of Cox-2 as a novel p63 target.2009In: The Journal of pathology, ISSN 1096-9896Article in journal (Refereed)
    Abstract [en]

    The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842). Copyright (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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  • 8.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Coates, Philip J
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    DeltaNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck.2007In: J Pathol, ISSN 0022-3417, Vol. 213, no 4, p. 384-91Article in journal (Refereed)
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  • 9.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Coates, Philip J
    Hedberg, Ylva
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Clinical Microbiology, Biomedical Laboratory Science.
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Dahlqvist, Åke
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.2005In: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 27, no 6, p. 1661-1667Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common malignancy in the world, is associated with smoking and has a low 5-year survival rate. Various changes have been described at different stages of SCCHN tumour development, including overexpression of p63, a protein important for development of normal epidermal structures. p63 has been suggested to activate beta-catenin, and nuclear accumulation of beta-catenin is an important event in many cancers. Elevated COX-2 activity and overexpression of EGFR protein has been shown in a variety of human cancers, including SCCHN. An important question for the pathogenesis of SCCHN is when the genetic changes take place during the natural course of the disease, and whether they appear in clinically normal oral mucosa to predispose tumour development. We mapped the expression of p63, COX-2, EGFR, beta-catenin, and PP2A in oral mucosa from smokers/non-smokers and from patients with SCCHN. We also considered if changes occurring in tumours are present in the clinically normal tissue adjacent to the tumour. No direct influence of heavy smoking on the levels of the proteins studied could be seen. Tumours and clinically normal non-neoplastic tissue from SCCHN patients showed increased expression of COX-2 and PP2A. Interestingly, non-neoplastic tissue adjacent to SCCHN also showed increased beta-catenin, although this was not seen in tumours. The data support the notion that pre-existing alterations in clinically normal epithelium exist in patients with SCCHN and could be important for the pathogenesis of the disease and for local recurrences.

  • 10.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Differences in p63 expression in SCCHN tumours of different sub-sites within the oral cavity2011In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 47, no 9, p. 861-865Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck, SCCHN, the sixth most common cancer in the world, comprises tumours of differentanatomical sites. The overall survival is low, and there are no good prognostic or predictive markers available. The p53 homologue, p63, plays an important role in development of epithelial structures and has also been suggested to be involved in development of SCCHN. However, most studies on p63 in SCCHN have not taken into account the fact that this group of tumours is heterogeneous in terms of the particular site of origin of the cancer. Mapping and comparing p63 expression levels in tumours and corresponding clinically normal tissue in SCCHN from gingiva, tongue and tongue/floor of the mouth revealed clear differences between these regions. In normal samples from tongue and gingiva, tongue samples showed 2.5-fold higher median p63 expression and also more widespread expression compared to gingival samples. These results emphasise the importance of taking sub-site within the oral cavity into consideration in analyses of SCCHN.

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  • 11.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    p63 transcriptionally regulates BNC1, a Pol I and Pol II transcription factor that regulates ribosomal biogenesis and epithelial differentiation2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no 9, p. 1401-1406Article in journal (Refereed)
    Abstract [en]

    The p53-family member, p63 is a transcription factor that influences cellular adhesion, motility, proliferation, survival and apoptosis, and has a major role in regulating epithelial stem cells. Expression of p63 is often dysregulated in squamous cell carcinomas of the head and neck. In this study we show that p63 induces the expression of the basal epithelial transcription factor, Basonuclin 1. Basonuclin 1 is an unusual transcription factor that interacts with a subset of promoters of genes that are transcribed by both RNA polymerase-I and -II and has roles in maintaining ribosomal biogenesis and the proliferative potential of immature epithelial cells. Chromatin immunoprecipitation and reporter assays demonstrate that Basonuclin 1 is a direct transcriptional target of p63 and we also show that up-regulation of Basonuclin 1 is a common event in squamous cell carcinomas of the head and neck. These data identify a new transcriptional programme mediated by p63 regulation of the Basonuclin 1 transcription factor in squamous cell carcinomas and provide a novel link of p63 with the regulation of ribosomal biogenesis in epithelial cancer.

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  • 12.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Tayside Tissue Bank Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
    Wahlgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins.2012In: Journal of Carcinogenesis, ISSN 0974-6773, E-ISSN 1477-3163, Vol. 11, p. 18-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools.

    MATERIALS AND METHODS: In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity.

    RESULTS: We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b.

    CONCLUSION: The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.

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  • 13.
    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, 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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  • 14.
    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, 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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  • 15. Brychtova, Veronika
    et al.
    Coates, Philip J.
    Hrabal, Vaclav
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fabian, Pavel
    Vojtesek, Borivoj
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Keratin 36, a specific marker of tongue filiform papillae, is downregulated in squamous cell carcinoma of the mobile tongue2020In: Molecular and clinical oncology, ISSN 2049-9450, E-ISSN 2049-9469, Vol. 12, no 5, p. 421-428Article in journal (Refereed)
    Abstract [en]

    Human keratin 36 (K36) is a member of the hair keratin family and is a marker of hair cortex differentiation. The human KRT36 gene is located on the long arm of chromosome 17 and belongs to the cluster of structurally unrelated acidic hair keratins. Recently, it has been reported that KRT36 mRNA is specifically expressed in normal tongue epithelium and downregulated in squamous cell carcinomas of the mobile tongue. Furthermore, KRT36 levels have been reported to be downregulated in clinically normal mobile tongue tissue that is adjacent to tumours, suggesting it could be a marker of pre-neoplastic changes. However, the exact role and the potential role of K36 in tongue tumour formation remains unclear. The aim of the present study was to investigate expression of K36 in a series of squamous cell carcinomas of the mobile tongue, normal mobile tongue and a small panel of other human tissues (normal tissue from the appendix, cervix, hair, lip, mamilla, nail, oesophagus, skin, thymus and vagina) and selected cancer tissue (cervical cancer, melanoma and basal cell carcinoma). Affinity purified polyclonal antibodies against K36 were generated and used for immunohistochemical analysis. The results revealed that in the normal tongue, K36 was detected specifically in the filiform papillae of the dorsal surface of the tongue. Additionally, none of the tongue cancer tissue samples were K36-positive. Immunostaining also revealed that K36 was expressed in nail beds, Hassal's corpuscles in the thymus and the hair cortex. However, K36 was not expressed in the squamous epithelia of the skin, cervix and oesophagus, and the squamous cells of cervical carcinomas, basal cell carcinoma or melanoma. The present data indicated that K36 may be inactivated in tumours of the tongue. However, whether this is part of the tumoural process or if it is an effect of the tumour itself remains to be elucidated.

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  • 16.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rentoft, Matilda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Coates, Philip
    Tayside Tissue Bank/Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Wahlin, Ylva Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Autoantibodies and decreased expression of the transcription factor ELF-3 together with increased chemokine pathways support an autoimmune phenotype and altered differentiation in lichen planus located in oral mucosa2013In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 27, no 11, p. 1410-1416Article in journal (Refereed)
    Abstract [en]

    Background  The pathogenesis of oral lichen planus (OLP), a chronic inflammatory disease, is not fully understood. It is known that OLP has autoimmune features, and it is suggested to be an autoimmune disease. ELF-3 is involved in differentiation of keratinocytes and deregulated in different tumours and inflammatory diseases. CXCR-3 and its ligands CXCL-10 and CXCL-11 are increased in autoimmune diseases and linked to Th-1 immune response. Objectives  To analyse and compare expression of ELF-3, CXCR-3, CXCL-10 and CXCL-11 in OLP lesions and controls in whole and microdissected epithelium. Methods  Tissue biopsies from 20 patients clinically and histologically diagnosed with OLP and 20 healthy controls were studied using whole tissues or microdissected epithelium. By the use of qRT-PCR, mRNA levels of ELF-3, CXCR-3, CXCL-10 and CXCL-11 were studied. Western blot was used for analysis of ELF-3 protein expression. Sera from 19 OLP patients and 20 controls were analysed with ELISA in search for autoantibodies. Results  The upregulation of CXCR-3, CXCL-10 and CXCL-11 found in OLP is similar to previous findings showing an autoimmune phenotype in lichen planus (LP) and lichen sclerosus. Decreased expression of the differentiation-related transcription factor ELF-3 was also seen in OLP lesions, and we further demonstrate presence of circulating autoantibodies against the ELF-3 protein in sera from 3 of 19 (16%) LP patients tested. Conclusions  On the basis of these findings, we confirm that OLP shows features of an autoimmune disease and suggest deregulated differentiation of keratinocytes to be one of the causes of the disease phenotype.

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  • 17.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Coates, Philip J
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Genes Involved in Epithelial Differentiation and Development are Differentially Expressed in Oral and Genital Lichen Planus Epithelium Compared to Normal Epithelium2014In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 94, no 5, p. 526-530Article in journal (Refereed)
    Abstract [en]

    Lichen planus (LP) is a chronic mucocutaneous disease with unknown cause. Patients with LP often have both oral and genital lesions, but these conditions are often considered as separate diseases and treated accordingly. To find out which genes are differently expressed in mucosal LP compared to normal mucosa and establish whether oral and genital LP are in fact the same disease, whole genome expression analysis was performed on epithelium from 13 patients diagnosed with oral and/or genital LP and normal controls. For confirmation of keratin 4 and corneodesmosin expression, quantitative reverse-transcription PCR and immunohistochemistry were used. Many genes involved in epithelial development and differentiation are differently expressed in epithelium from LP compared to normal epithelium. Several of the differentially expressed genes are common for oral and genital LP and the same biological processes are altered which supports the fact that oral and genital LP are manifestations of the same disease. The change in gene expression indicates that differentiation is altered leading to changes in the epithelial barrier.

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  • 18.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ebrahimi, Maijd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Increased levels of COX-2 in oral lichen planus supports an autoimmune cause of the disease2012In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 26, no 11, p. 1415-1419Article in journal (Refereed)
    Abstract [en]

    Background: Oral lichen planus (OLP) is a chronic inflammatory disease for which the pathogenesis is not fully understood. OLP has autoimmune features and auto immunity has been suggested as a potential cause, whereas WHO has classified OLP as a premalignant condition. Association between chronic inflammation and cancer is known and chronic inflammation is one of the characteristics of OLP. A protein connected to inflammation and suggested to be involved in cancer development is cyclooxygenase-2 (COX-2) which can be inhibited by microRNA-26b (miR-26b).

    Objective: The aim was to map levels of COX-2 and miR-26b in OLP lesions to see if there was any correlation between expression of COX-2 and its regulator miR-26b in OLP.

    Methods: In biopsies from 20 OLP patients and 20 age and gender-matched controls laser- micro dissection of epithelium was performed. Quantitative RT-PCR, immunohistochemistry and Western blot were used in the analysis.

    Results: Levels of COX-2 mRNA were significantly higher while levels of miR-26b were significantly lower in OLP lesions compared to controls. Using immunohistochemistry normal oral mucosa samples did not show any expression of COX-2 while OLP samples expressed the protein. No COX-2 protein was detectable with Western blot.

    Conclusion: Increased expression of COX-2 and decreased expression of miR-26b in OLP suggests both to play a role in OLP. COX-2 has been connected to both malignant development and autoimmunity but as malignant development of OLP is quite rare we suggest that the increased levels of COX-2 seen here support an autoimmune cause of the disease.

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  • 19.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Wahlin, Ylva Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Alterations in factors involved in differentiation and barrier function in the epithelium in oral and genital lichen planus2017In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, no 2, p. 214-218Article in journal (Refereed)
    Abstract [en]

    Lichen planus is a chronic recurrent inflammatory disease affecting both skin and mucosa, mainly in oral and/or genital regions. Keratinocytes go through a well-regulated process of proliferation and differentiation, alterations in which may result in defects in the protective epithelial barrier. Long-term barrier impairment might lead to chronic inflammation. In order to broaden our understanding of the differentiation process in mucosal lichen planus, we mapped the expression of 4 factors known to be involved in differentiation. Biopsies were collected from oral and genital lichen planus lesions and normal controls. Altered expression of all 4 factors in epithelium from lichen planus lesions was found, clearly indicating disturbed epithelial differentiation in lichen planus lesions.

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  • 20.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Diagnostics.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Diagnostics. Umeå University, Faculty of Medicine, Department of Odontology, Endodontics.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Diagnostics. Umeå University, Faculty of Medicine, Department of Odontology, Prosthetic Dentistry.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Reply to increased levels of COX-2 and oral lichen planus by P.D. Pigatto, F. Spaderi, G.P. Bombeccari, G. Guzzi by Danielsson et al2013In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 27, no 3, p. 395-396Article in journal (Refereed)
    Publisher's full text
  • 21.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wahlin, Ylva Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Coates, PJ
    Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa2010In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 39, no 9, p. 639-644Article in journal (Refereed)
    Abstract [en]

    Backgound: Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa which the World Health Organisation (WHO) considers a premalignant condition. One step in malignant development is so called epithelial mesenchymal transition (EMT), a process whereby epithelial cells acquire mesenchymal characteristics. EMT occurs during embryogenesis and wound healing but also in some human diseases such as cancer and fibrosis. A factor known to induce EMT is transforming growth factor-beta (TGF-beta), which uses the Smad proteins as mediators for its signalling. TGF-beta is also often over-expressed in squamous cell carcinoma of the head and neck (SCCHN).

    Methods: In the present study we mapped expression of Smad proteins in OLP lesions by immunohistochemistry, and compared to expression in normal and sensitive oral mucosa. The latter group of patients had developed SCCHN after shorter or longer periods of diffuse oral symptoms. The aim was to see if there were any signs of EMT related changes in the OLP lesions, as judged by changes in the TGF-beta pathway.

    Conclusion: Changes in the TGF-beta pathway related to EMT are seen in the very earliest stages of oral malignancy and become more severe as lesions progress.

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  • 22.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Diagnostics.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Diagnostics. Umeå University, Faculty of Medicine, Department of Odontology, Prosthetic Dentistry.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Decreased expression of ELF-3 indicating disturbed differentiation in oral lichen planus2012In: Oral Diseases, ISSN 1354-523X, E-ISSN 1601-0825, Vol. 18, no Special Issue, Suppl. 1, p. 20-20Article in journal (Other academic)
  • 23.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Altered expression of miR-21, miR-125b, and miR-203 indicates a role for these microRNAs in oral lichen planus2012In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, no 1, p. 90-95Article in journal (Refereed)
    Abstract [en]

    Background: Oral lichen planus (OLP), which is a chronic inflammatory disease of the oral mucosa with unknown etiology, affects about 2% of the population. MicroRNAs are small non-coding RNAs involved in normal processes such as development and differentiation as well as progression of human diseases. The aim of this study was to investigate the expression of miR-21, miR-125b, and miR-203 and to compare RNA levels of their potential targets, the tumor suppressor p53 and its relative p63, both known to be deregulated in OLP.

    Methods: In biopsies from 20 patients with OLP and 20 age- and sex-matched healthy controls, epithelium was laser dissected and analyzed for the expression of miR-21, miR-125b, miR-203, p53, and p63 using qRT/PCR.

    Results: Increased expression of miR-21 and miR-203, decreased expression of miR-125, and down-regulation of p53 and ΔNp63 RNA were seen in OLP compared to normal oral mucosa. When comparing microRNA expression to levels of p53 and p63 RNA, a significant negative correlation was seen between ΔNp63 and miR-203 and between miR-21 and p53, respectively.

    Conclusion: Results indicate a role for the studied microRNAs in changes seen in OLP.

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  • 24. Daskalogianni, Chrysoula
    et al.
    Pyndiah, Slovenie
    Apcher, Sebastien
    Mazars, Anne
    Manoury, Benedicte
    Ammari, Nisrine
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Voisset, Cecile
    Blondel, Marc
    Fahraeus, Robin
    Epstein-Barr virus-encoded EBNA1 and ZEBRA: targets for therapeutic strategies against EBV-carrying cancers2015In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 2, p. 334-341Article, review/survey (Refereed)
    Abstract [en]

    The EBV-encoded EBNA1 was first discovered 40 years ago, approximately 10 years after the presence of EBV had been demonstrated in Burkitt's lymphoma cells. It took another 10 years before the functions of EBNA1 in maintaining the viral genome were revealed, and it has since been shown to be an essential viral factor expressed in all EBV-carrying cells. Apart from serving to maintain the viral episome and to control viral replication and gene expression, EBNA1 also harbours a cis-acting mechanism that allows virus-carrying host cells to evade the immune system. This relates to a particular glycine-alanine repeat (GAr) within EBNA1 that has the capacity to suppress antigen presentation to the major histocompatibility complex (MHC) class I pathway. We discuss the role of the GAr sequence at the level of mRNA translation initiation, rather than at the protein level, as at least part of the mechanism to avoid MHC presentation. Interfering with this mechanism has become the focus of the development of immune-based therapies against EBV-carrying cancers, and some lead compounds that affect translation of GAr-carrying mRNAs have been identified. In addition, we describe the EBV-encoded ZEBRA factor and the switch from the latent to the lytic cycle as an alternative virus-specific target for treating EBV-carrying cancers. Understanding the molecular mechanisms of how EBNA1 and ZEBRA interfere with cellular pathways not only opens new therapeutic approaches but continues to reveal new cell-biological insights on the interplay between host and virus. This review is a tale of discoveries relating to how EBNA1 and ZEBRA have emerged as targets for specific cancer therapies against EBV-carrying diseases, and serves as an illustration of how mRNA translation can play roles in future immune-based strategies to target viral disease. 

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  • 25. de Almeida, Fernando J. Mota
    et al.
    Kivijarvi, Kristina
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    A case of disseminated histoplasmosis diagnosed after oral presentation in an old HIV-negative patient in Sweden2015In: Gerodontology, ISSN 0734-0664, E-ISSN 1741-2358, Vol. 32, no 3, p. 234-236Article in journal (Refereed)
    Abstract [en]

    Histoplasmosis is an endemic disease in various regions such as North America and South-East Asia but remains rare in Europe. Disseminated histoplasmosis is unusual in HIV-negative patients. Here, we describe a case of disseminated histoplasmosis in an HIV-negative patient diagnosed after oral presentation.

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  • 26.
    Ebrahimi, Majid
    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
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral and Maxillofacial Radiology.
    Bourdon, Jean-Christophe
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of novel p53 isoforms in oral lichen planus.2007In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 44, no 2, p. 156-161Article in journal (Refereed)
    Abstract [en]

    Oral lichen planus (OLP) is a chronic inflammatory disease of unknown origin, showing little spontaneous regression. WHO classifies OLP as a premalignant condition, however, the underlying mechanisms initiating development of cancer in OLP lesions are not understood. The p53 tumour suppressor plays an important role in many tumours, and an increased expression of p53 protein has been seen in OLP lesions. Recently it was shown that the human TP53 gene encodes at least nine different isoforms. Another member of the p53 family, p63, comprises six different isoforms and plays a crucial role in the formation of oral mucosa, salivary glands, teeth and skin. It has also been suggested that p63 is involved in development of squamous cell carcinoma of the head and neck (SCCHN). In contrast to p53, a decreased expression of p63 protein has been seen in OLP lesions. In this study, we mapped the expression of five novel p53 isoforms at RNA and protein levels in OLP and matched normal controls. In the same samples we also measured levels of p63 isoforms using quantitative RT-PCR. Results showed p53 to be expressed in all OLP lesions and normal tissues. The p53beta and Delta133p53 isoforms were expressed in the majority of samples whereas the remaining three novel isoforms analysed were expressed in only a few samples. Levels of p63 isoforms were lower in OLP lesions compared with normal tissue, however, changes were not statistically significant.

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  • 27.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Pediatric Dentistry.
    Coates, Philip J
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Decreased expression of the p63 related proteins beta-catenin, E-cadherin and EGFR in oral lichen planus2007In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 44, no 7, p. 634-638Article in journal (Refereed)
    Abstract [en]

    Oral lichen planus (OLP) is a chronic inflammatory disease and although classified by WHO as a premalignant condition, the risk for transformation into squamous cell carcinoma of the head and neck (SCCHN) is a matter of great controversy. The p63 gene encodes six different proteins which are required for development of ectodermally derived tissues such as oral mucosa, salivary glands, teeth and skin. p63 is highly expressed in SCCHN whereas decreased expression is seen in OLP. beta-catenin, E-cadherin and epidermal growth factor receptor (EGFR) are p63 related proteins, and abnormalities in their expression suggested they are involved in development of squamous cell carcinoma of the head and neck (SCCHN). In this study we mapped the expression of these p63 related proteins in OLP and matched normal healthy controls. Results showed decreased expression of beta-catenin, E-cadherin and EGFR in the vast majority of OLP samples compared with the normal controls. This is the first comprehensive study mapping expression of several p63- and SCCHN-related proteins in tissue from patients with OLP. Results showed a mixed expression pattern with OLP variably resembling normal as well as tumour tissue. Based on our present and previous data it cannot be judged whether OLP lesions are at an increased risk of malignant development.

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  • 28.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Endodontics.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Bäcklund, Bodil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Coates, Philip J
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The use of a novel ELISA method for detection of antibodies against p63 in sera from patients diagnosed with oral and/or genital and skin lichen planus.2010In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714Article in journal (Refereed)
    Abstract [en]

    Lichen planus is a chronic inflammatory disease of mucosa and skin affecting approximately 1-2% of the adult population. Autoimmunity has been implicated in the etiology of this disease, and recently we detected antibodies directed against all six p63 isoforms in sera from 2 out of 20 patients diagnosed with oral lichen planus (OLP) using Western blot analysis. Here we have developed an ELISA method for screening sera for presence of autoantibodies directed against p63. Using the same sera as previously analysed, we show that the optical density ratios for sera from the two patients with known autoantibodies was considerably higher compared to mean optical density ratios for all samples as well as controls analysed. Applying this novel ELISA technique for screening of sera from an additional group of 46 patients with oral and/or genital or skin lichen and 43 matched controls, we detected another three patients with autoantibodies against the p63 proteins. These data are discussed together with the observation that all five patients with detectable p63 autoantibodies from our two studies had clinically severe disease symptoms.

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  • 29.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    van der Waal, Isaäc
    Department of Oral and Maxillofacial Surgery, Academic Centre for Dentistry Amsterdam .
    Letter to the editor: Reply to H. M. Ögmundsdóttir & W. P. Holbrook by M. Ebrahimi et al.2011In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 9, p. 732-Article in journal (Refereed)
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  • 30.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Endodontics.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Der Waal, Isaäc
    Oral lichen planus and the p53 family: what do we know?2011In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 4, p. 281-285Article in journal (Refereed)
    Abstract [en]

    J Oral Pathol Med (2010) Oral lichen planus (OLP) is a relatively common chronic disease of the oral mucosa for which the aetiopathogenesis is not fully understood. It mainly affects middle aged and elderly. The finding of autoantibodies against p63, a member of the p53 family, is a strong indication of autoimmunity as a causative or contributing factor. The WHO classified OLP as a potentially malignant disorder, but still there is an ongoing debate in the literature on this subject. The TP53 gene encodes a tumour suppressor protein that is involved in induction of cell-cycle arrest or apoptosis of DNA-damaged cells. The p63 gene encodes six different proteins that are crucial for formation of the oral mucosa and skin. The coordinated stabilization of p53 and decreased expression of p63 seen in OLP cause induction of apoptosis enabling removal of DNA-damaged cells. In view of the complexity of cancerogenesis, no firm statement can at present be made about the relevance of the observed relationship between p53 and p63 and the possible malignant transformation of OLP.

    Publisher's full text
  • 31.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral and Maxillofacial Radiology.
    Coates, Philip J
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Decreased expression of p63 in oral lichen planus and graft-vs.-host disease associated with oral inflammation.2006In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 35, no 1, p. 46-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oral lichen planus (OLP) and graft-vs.-host disease (GVHD) are conditions with increased risk of malignant transformation to squamous cell carcinoma of the head and neck (SCCHN). The p63 gene encodes six different proteins and is expressed at high levels in SCCHN. METHODS: Biopsies from patients diagnosed with OLP and GVHD were analysed for p63 protein expression using antibodies distinguishing between the major isoforms expressed in normal epithelia, in parallel with biopsies from normal buccal mucosa and SCCHN. RESULTS: In OLP and GVHD a decreased expression of all p63 isoforms was seen, while expression of p53 protein was upregulated, compared with normal mucosa. In SCCHN, p63 was abundantly expressed and some tumours showed strong p53 staining, suggestive of p53 mutation. CONCLUSIONS: Decreased p63 and increased p53 expression in OLP and GVHD indicates a coordinated action of these two related proteins to protect the oral mucosae from the damaging effects of underlying inflammation. In SCCHN disruption of the TP53 gene and overrepresentation of certain p63 isoforms

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  • 32.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Odontology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral and Maxillofacial Radiology.
    Coates, Philip J
    Wiik, Allan
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Detection of antibodies against p63 and p73 isoforms in sera from patients diagnosed with oral lichen planus.2007In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 36, no 2, p. 93-98Article in journal (Refereed)
    Abstract [en]

    Background: Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa. Despite numerous publications and intense research, the etiology of OLP is still unknown, however, autoimmunity as a possible causative factor has been discussed. Methods: In the present study sera from 20 patients clinically and histologically diagnosed with OLP were analyzed for antibodies directed toward p53, p63, and p73 using Western blot. Results: Sera from two patients reacted with all six p63 isoforms, and one also with p73. The strongest reaction was noted against the TAp63beta protein, which is the most potent transactivator of all p63 proteins and is implicated in the differentiation of stratified epithelia. Conclusions: This is the first demonstration of antibodies directed against all p63 and some p73 isoforms in sera from patients diagnosed with OLP.

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  • 33. 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, 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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  • 34.
    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, 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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  • 35.
    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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  • 36.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bäckman, Birgitta
    Umeå University, Faculty of Medicine, Odontology, Pediatric Dentistry.
    Coates, Philip J
    Cullman, Inger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Exclusion of p63 as a candidate gene for autosomal-dominant amelogenesis imperfecta.2006In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 64, no 2, p. 111-114Article in journal (Refereed)
    Publisher's full text
  • 37.
    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.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck2008In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 263, no 1, p. 26-34Article in journal (Refereed)
    Publisher's full text
  • 38.
    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]