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  • 1.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head & Neck Surgery, and Medical Biochemistry, University of Turku, Finland.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer2009In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 1, p. 23-29Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the predisposition of the FGFR4 Gly/Arg polymorphism for development of head and neck squamous cell carcinoma (HNSCC) and, furthermore, to examine if the FGFR4 Arg(388) allele can be associated with resistance to chemo-and radiotherapy.

    When analysing 110 tumour biopsies a significant 1.7-fold increased risk to develop HNSCC in individuals carrying the Gly(388) allele (p = 0.026) was found. Moreover a 2-fold increased risk for mates harbouring the Gly(388) allele (p = 0.031) to develop HNSCC was detected. In 39 HNSCC cell lines the role of the Arg(388) allele for radiation and cisplatin sensitivity was investigated. Our results show no rote of the Arg(388) allele for the radiosensitivity (p = 0.996) but indicate a tendency to increased cisplatin sensitivity (p = 0.141). When screening the transmembrane and kinase domains in the FGFR4 gene a novel mutation, probably generating a truncated protein lacking exons 14-18, was found in six of eight selected cell lines.

    Taken together, we have here identified a marker that predicts the risk to develop HNSCC and possibly the sensitivity to cisplatin as well as a novel. mutation in the FGFR4 gene.

  • 2.
    Djerf, Emelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Abdiu, Avni
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Walz, Thomas M
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)2009In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, ISSN 0960-8931, Vol. 19, no 3, p. 156-166Article in journal (Refereed)
    Abstract [en]

    Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 mu mol/l, respectively. Cell growth was inhibited at 0.1 mu mol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 mu mol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G, phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27(KIP1). There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.

  • 3.
    Eklund, Lena
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Skin cancer is the most common type of cancer in the western world. The incidence of melanoma and non-melanoma skin cancer is continuously increasing and, in Sweden, 2300 new cases per year are diagnosed of squamous cell carcinoma (SCC) alone. In this thesis, we have investigated genes and proteins from signal transduction pathways important for tumor development. Special emphasis has been put on chromosomal region 9q22-q31 where frequent loss of heterozygosity has been observed in non-melanoma skin cancers.

    Mutation analysis of the PTCH1 and XPA genes, connected to the familial cancer syndromes nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, respectively, was performed. Based on lack of mutation or altered mRNA expression, we conclude that these two genes are not likely to be involved in development of sporadic SCCs. Next, we studied the correlation of the two phenotypes, anchorage independence and tumorigenicity, to the loss of chromosome 9 material in a panel of somatic cell hybrids. By microsatellite analysis, we show that the anchorage independence gene is located distal to the marker D9S155. The mapping of the gene for tumor suppression revealed three commonly deleted regions on chromosome regions 9p23-p22, 9p21-p12 and 9q31-q33. Another two candidates from the 9q22-q31 region, CORO2A and TßR-I, were investigated both at the gene and the protein level. We did not detect any alterations in the TßR-I gene or protein, but CORO2A protein was over-expressed in 4 of 40 (10%) tumors, indicating an involvement in sec carcinogenesis in a subset of tumors. In one healthy individual from the control population, we found a heterozygous germline mutation in CORO2A creating a stop codon, which results in a truncated protein. Thus, one functional allele might be sufficient to sustain a normal cellular function. When investigating occurrence of aberrant protein expression in the interconnected Wnt and Notch pathways, Notch1 was found to be expressed in only 5 of 40 (14%) of the normal epidermal cells, while strong staining was displayed in all the tumors. No altered expression of the most central protein of the Wnt pathway, ß-catenin, was observed, but the up-stream Dvl-1 protein was found to be up-regulated in 8 of 38 (21%) tumors. Dvl-1 was also detected in the nucleus in the majority of normal and tumor cases and a potential nuclear localization signal was identified in the Dvl-1 A isoform.

    None of the genes from the chromosomal region 9q22-q31 displayed alterations consistent with those of a tumor suppressor gene. Most likely, this gene remains to be identified.

    List of papers
    1. Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
    Open this publication in new window or tab >>Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
    Show others...
    1998 (English)In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 21, no 2, p. 87-92Article in journal (Refereed) Published
    Abstract [en]

    The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis. 

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85078 (URN)10.1002/(SICI)1098-2744(199802)21:2<87::AID-MC2>3.0.CO;2-L (DOI)
    Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2017-12-07
    2. Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 9
    Open this publication in new window or tab >>Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 9
    2001 (English)In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 130, no 2, p. 118-126Article in journal (Refereed) Published
    Abstract [en]

    By microcell-mediated chromosome transfer to the malignant Syrian hamster cell line BHK-191-5C, we previously identified two suppressor functions on human chromosome 9 (HSA9), one for anchorage independence and another for tumorigenicity. However, the precise chromosomal locations of these suppressor functions were not determined. The present study was undertaken to define the regional location of these suppressor loci using a panel of microcell hybrids containing structurally altered HSA9 with different deleted regions in the BHK-191-5C background. DNA derived from the cell hybrids was analyzed by PCR for verification of the presence of HSA9 genetic material by amplifying 62 microsatellite markers and 13 genes, covering the entire length of HSA9. Our deletion mapping data on anchorage independent and tumorigenic hybrids suggest that the suppressor function for anchorage independence is located in the region between 9q32 to 9qter. The suppressor for tumorigenicity may be located in one of three deleted regions on HSA9, the first one between the markers D9S162 and D9S1870, the second one between the markers D9S1868 and TIGRA002I21, and the third one between the markers D9S59 and D9S155.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25000 (URN)10.1016/S0165-4608(01)00471-X (DOI)9420 (Local ID)9420 (Archive number)9420 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    3. Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skin
    Open this publication in new window or tab >>Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skin
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Allelic losses in several regions of chromosome 9q have been connected to the development of squamous cell carcinoma (SCC) of the skin. We have studied two candidate genes in the 9q22 region using mutational analysis of genomic DNA as well as immunohistochemistry for assessment of changes in protein expression. The coronin 2A (CORO2A) protein shows strong resemblance to actin-binding proteins, implying a role in cytokinesis or cell motility. It has also been found to be part of the nuclear receptor co-repressor complex involved in transcriptional regulation. We elucidated the exon-intron structure by sequence alignment of the mRNA to a "high-throughput genomic sequence" entry in GenBank. By using single strand conformation analysis and DNA sequencing we found eight silent mutations in tumor DNA, one of which was found in a subset of a normal control population. Surprisingly, immunostaining revealed over-expression in 4/40 tumors. This cannot explain the high frequency of allelic loss in cutaneous secs, but is yet indicating a possible involvement of CORO2A in cutaneous SCC development. The gene for transforming growth factor ß receptor 1 (TßR-I) has previously been positioned to the 9q22 region. TßR-I is part of a protein complex necessary for binding of the TGFß ligand initiating a signaling cascade, which affects downstream targets important for cell cycle regulation. We could not identify any alterations at either protein or DNA level and therefore exclude TßR-I as candidate for cutaneous sec development.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85099 (URN)
    Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02
    4. Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skin
    Open this publication in new window or tab >>Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skin
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

    Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

    Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

    Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

    Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85100 (URN)
    Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02
  • 4.
    Eklund, Lena
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Islam, Khaleda
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Islam, Quamrul
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 92001In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 130, no 2, p. 118-126Article in journal (Refereed)
    Abstract [en]

    By microcell-mediated chromosome transfer to the malignant Syrian hamster cell line BHK-191-5C, we previously identified two suppressor functions on human chromosome 9 (HSA9), one for anchorage independence and another for tumorigenicity. However, the precise chromosomal locations of these suppressor functions were not determined. The present study was undertaken to define the regional location of these suppressor loci using a panel of microcell hybrids containing structurally altered HSA9 with different deleted regions in the BHK-191-5C background. DNA derived from the cell hybrids was analyzed by PCR for verification of the presence of HSA9 genetic material by amplifying 62 microsatellite markers and 13 genes, covering the entire length of HSA9. Our deletion mapping data on anchorage independent and tumorigenic hybrids suggest that the suppressor function for anchorage independence is located in the region between 9q32 to 9qter. The suppressor for tumorigenicity may be located in one of three deleted regions on HSA9, the first one between the markers D9S162 and D9S1870, the second one between the markers D9S1868 and TIGRA002I21, and the third one between the markers D9S59 and D9S155.

  • 5.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Erika
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Undén, Anne Birgitte
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden and Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Lundh-Rozell, Barbro
    Department of Pathology, Huddinge University Hospital, Huddinge, Sweden.
    Ståhle-Bäckdahl, Mona
    Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Zaphiropoulos, Peter G.
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Toftgård, Rune
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin1998In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 21, no 2, p. 87-92Article in journal (Refereed)
    Abstract [en]

    The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis. 

  • 6.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lirvall, M.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skinManuscript (preprint) (Other academic)
    Abstract [en]

    Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

    Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

    Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

    Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

    Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

  • 7.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Undén, Anne Birgitte
    Karolinska Intitute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden and Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Lundin, Kristing B.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Zaphiropoulos, Peter G.
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Toftgård, Rune
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skinManuscript (preprint) (Other academic)
    Abstract [en]

    Allelic losses in several regions of chromosome 9q have been connected to the development of squamous cell carcinoma (SCC) of the skin. We have studied two candidate genes in the 9q22 region using mutational analysis of genomic DNA as well as immunohistochemistry for assessment of changes in protein expression. The coronin 2A (CORO2A) protein shows strong resemblance to actin-binding proteins, implying a role in cytokinesis or cell motility. It has also been found to be part of the nuclear receptor co-repressor complex involved in transcriptional regulation. We elucidated the exon-intron structure by sequence alignment of the mRNA to a "high-throughput genomic sequence" entry in GenBank. By using single strand conformation analysis and DNA sequencing we found eight silent mutations in tumor DNA, one of which was found in a subset of a normal control population. Surprisingly, immunostaining revealed over-expression in 4/40 tumors. This cannot explain the high frequency of allelic loss in cutaneous secs, but is yet indicating a possible involvement of CORO2A in cutaneous SCC development. The gene for transforming growth factor ß receptor 1 (TßR-I) has previously been positioned to the 9q22 region. TßR-I is part of a protein complex necessary for binding of the TGFß ligand initiating a signaling cascade, which affects downstream targets important for cell cycle regulation. We could not identify any alterations at either protein or DNA level and therefore exclude TßR-I as candidate for cutaneous sec development.

  • 8.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jedlinski, Adam
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ansell, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grenman, Reidar
    University of Turku.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines2009In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 24, no 4, p. 549-556Article in journal (Refereed)
    Abstract [en]

    The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).

  • 9.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland C
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grénman, Reidar
    Medical Biochemistry, University of Turku, Finland.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines2011In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 10, p. 739-746Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

    METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

    RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

    CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

  • 10.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernstrom, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ansell, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck2015In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 31, p. 64-72Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.

  • 11.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Tiefenböck, Katharina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ansell, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 8, p. 1994-2003Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Todays standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p andlt; 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC. less thanbrgreater than less thanbrgreater thanWhats new? Resistance to radiation therapy is a significant problem in the treatment of head and neck squamous cell carcinoma (HNSCC) and has created a need for the discovery of markers predictive of radiotherapy response. One promising marker is survivin, an inhibitor of apoptosis. Here, in pre-treatment biopsies from 40 patients with HNSCC, strong survivin expression was significantly associated with response to radiotherapy and increased overall survival. The data also indicate that single nucleotide polymorphisms in the genes XPD and FGFR4 are other possible predictors of overall survival after radiotherapy.

  • 12.
    Garvin, Stina
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Tiefenböck, Katharina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Farnebo, Marianne
    Karolinska Institute, Sweden.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma2015In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 51, no 1, p. 24-30Article in journal (Refereed)
    Abstract [en]

    Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

  • 13.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Khan, Muhammad Suleman
    COMSATS Institute of Information Technology, Abbottabad, Pakistan.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nahi, Hareth
    Karolinska University Hospital and Karolinska Institutet, Huddinge, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Association of CYP2B6 Genotype with Survival and Progression Free Survival in Cyclophosphamide Treated Multiple Myeloma2012In: Journal of Cancer Therapy, ISSN 2151-1934, E-ISSN 2151-1942, Vol. 3, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST en-zymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion:

    The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.

  • 14.
    Stjernstrom, Annika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Christina
    University of Örebro, Sweden.
    Fernandez, Oswaldo J.
    Örebro University Hospital, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Karlsson, Mats G.
    University of Örebro, Sweden; Örebro University Hospital, Sweden.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 2, p. 337-348Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate how alterations in the PI3K pathway correlate with non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation and protein expression of INPP4B, protein expression of pAkt, PDPK1, and PTEN and mutational status of PIK3CA and PTEN in 180 cases. Nineteen% displayed loss of INPP4B copy, whereas 47% lacked expression, both showing correlation with SCC. Elevated pAkt expression was seen in 63% of all cases, also correlating to SCC. PDPK1 was expressed in 70%, more in male than female patients. Regarding PTEN, 50% displayed loss of expression, of which seven were identified with mutations in the phosphatase domain. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC. When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA. Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression. As comparison, we also analyzed mitogen-activated protein kinase (MAPK) pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. No association was found to the Gly972Arg polymorphism of IRS-1, involved in activation of both PI3K and MAPK pathways. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of SCC of the lung.

  • 15.
    Thunell, Lena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Stjernstrom, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Synnerstad, Ingrid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Enerbäck, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma2014In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 24, no 3, p. 190-197Article in journal (Refereed)
    Abstract [en]

    The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR-restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma.

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