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  • 1.
    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)
  • 2.
    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.

  • 3.
    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.

  • 4.
    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)
  • 5.
    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, 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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    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)
  • 14.
    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)
  • 15.
    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.

  • 16.
    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.

  • 17.
    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.

  • 18.
    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.

  • 19.
    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)
  • 20.
    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. 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.
    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.

  • 21.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip
    MacCallum, Stephanie
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN2007In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 6, no 12, p. 1979-1983Article in journal (Refereed)
    Abstract [en]

    p63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.

  • 22.
    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.

  • 23.
    Li, Xingru
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ottosson, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wilms' tumor gene 1 regulates p63 and promotes cell proliferation in squamous cell carcinoma of the head and neck2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 342Article in journal (Refereed)
    Abstract [en]

    Background: Wilms' tumor gene 1 (WT1) can act as a suppressor or activator of tumourigenesis in different types of human malignancies. The role of WT1 in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Overexpression of WT1 has been reported in SCCHN, suggesting a possible oncogenic role for WT1. In the present study we aimed at investigating the function of WT1 and its previously identified protein partners p63 and p53 in the SCCHN cell line FaDu. Methods: Silencing RNA (siRNA) technology was applied to knockdown of WT1, p63 and p53 in FaDu cells. Cell proliferation was detected using MTT assay. Chromatin immunoprecipitation (ChIP)/PCR analysis was performed to confirm the effect of WT1 on the p63 promoter. Protein co-immunoprecipitation (co-IP) was used to find protein interaction between WT1 and p53/p63. Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63. WT1 RNA level was detected using real-time quantitative PCR (RT-qPCR) in patients with SCCHN. Results: We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation. We reported a novel positive correlation between WT1 and p63 expression. Subsequently, p63 was identified as a WT1 target gene. Furthermore, expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication was significantly altered by downregulation of WT1 and p63 expression. Several known WT1 and p63 target genes were affected by WT1 knockdown. Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63. Additionally, high WT1 mRNA levels were detected in SCCHN patient samples. Conclusions: Our findings suggest that WT1 and p63 act as oncogenes in SCCHN, affecting multiple genes involved in cancer cell growth.

  • 24.
    Nylander, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    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, Endodontics.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Changes in miRNA expression in sera and correlation to duration of disease in patients with multifocal mucosal lichen planus.2012In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, no 1, p. 86-89Article in journal (Refereed)
    Abstract [en]

    Background: Mucosal lichen planus is a severe variant of lichen planus, Lichen planus (LP), which in many ways affect patients' lives. The aetiology is not fully understood, and there is no treatment clearing the disease once and for all. Oral LP has by the WHO been classified as a precancerous lesion. Micro-RNAs, miRNAs, are non-coding, small single-stranded RNAs involved in biological processes like apoptosis, proliferation, differentiation, metastasis, angiogenesis and immune response.

    Methods and Results: In sera from 30 patients with multifocal mucosal LP, 15 miRNAs were identified as significantly differentially expressed compared with controls. The three most up-regulated miRNAs are all connected to oral squamous cell carcinoma or epithelial carcinoma in general.

    Discussion: Even if no specific LP-associated miRNA profile was found, data clearly indicate that miRNAs could play a role in the earlier phases of lichen planus.

  • 25.
    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.

  • 26.
    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.

  • 27.
    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.

  • 28.
    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.

  • 29.
    Thurfjell, Niklas
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Coates, Philip J
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Lindgren, Britta
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bäcklund, Bodil
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Uusitalo, Tony
    Mahani, David
    Dabelsteen, Erik
    Dahlqvist, Åke
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Vojtesek, Borek
    Nenutil, Rudolf
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Function and importance of p63 in normal oral mucosa and squamous cell carcinoma of the head and neck.2005In: Advances in Oto-Rhino-Laryngology, ISSN 0065-3071, E-ISSN 1662-2847, Vol. 62, p. 49-57Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS: Squamous cell carcinoma of the head and neck (HNSCC) is the 6th most common malignancy worldwide with a 5-year survival that has not improved over the last 20-25 years. Factors of prognostic significance for this tumour type include the presence of regional lymph node metastasis and amplification of chromosome 3q21-29, where the p63 gene is located. This gene encodes 6 proteins and is crucial for formation of the oral mucosa, teeth, salivary glands and skin. Each of the 6 different p63 proteins has different characteristics and functions, where some resemble the tumour suppressor protein p53, whilst others have functions that oppose p53. METHODS: To understand the function and importance of p63 in oral mucosa and tumour development we have studied protein as well as mRNA expression in normal oral mucosa and tumours. RESULTS/CONCLUSION: Expression of p63 proteins differs between the cell layers in normal oral mucosa, and primary HNSCC has a high expression level of p63 isoforms normally expressed in basal cells. Data suggest that p63 expression in HNSCC influences tumour cell differentiation.

  • 30. Troiano, Giuseppe
    et al.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ardito, Fatima
    Gu, Xaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lo Muzio, Lorenzo
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Circulating miRNAs from blood, plasma or serum as promising clinical biomarkers in oral squamous cell carcinoma: A systematic review of current findings2016In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 63, p. 30-37Article, review/survey (Refereed)
    Abstract [en]

    The purpose of this systematic review was to summarize current findings on the use of circulating miRNAs from blood, serum and plasma as cancer biomarkers in patients with oral squamous cell carcinoma. Studies were gathered after searching four different electronic databases: PUBMED, SCOPUS, Cochrane Library and Web of Science. Additional search was carried out through cross check on bibliography of selected articles. After the selection process made by two of the authors, 16 articles met the inclusion criteria and were included in the review. Results showed that circulating miRNAs from blood, serum or plasma represent promising candidates as cancer biomarkers in patients suffering from oral cancer. The possibility to predict recurrences and metastases through follow-up quantification of candidate miRNAs represents another potential feature to be addressed in future studies. However, methodological standardization and uniform sampling is needed to increase the power and accuracy of results. 

  • 31. Troiano, Giuseppe
    et al.
    Caponio, Vito Carlo Alberto
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lo Muzio, Lorenzo
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of the long non-coding RNA HOTAIR as a prognostic factor in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 42, p. 73029-73036Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Long noncoding RNAs (lncRNAs) are often dysregulated in cancer tissue and seem to play an important role in neoplastic processes. Recent studies have shown that the HOX transcript antisense intergenic RNA (HOTAIR) may play a role as a marker of prognosis in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to perform a meta-analysis of studies focused on the prognostic role of HOTAIR in SCCHN.

    Results: At the end of the selection process, four studies were considered eligible for inclusion in the meta-analysis, comprising a total of 271 patients. Meta-analysis revealed that high expression of HOTAIR was associated with poor overall survival (HR, 1.90; 95% CI: [1.42, 2.53]; p < 0,0001), advanced tumor stage (OR, 3.44; 95% CI: [1.84, 6.43]; p < 0,001) and lymph-node metastasis (OR, 3.31; 95% CI: [1.24, 8.79]; p = 0,02).

    Materials and Methods: The literature search was performed in the following databases: PUBMED, SCOPUS, EMBASE and Web of Science, in order to find studies that met the inclusion criteria.

    Conclusions: Findings from this systematic review and meta-analysis revealed that HOTAIR represents a potential biomarker of prognosis in patients with squamous cell carcinoma of the head and neck.

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