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  • 1.
    Baust, H.
    et al.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Schoke, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Brey, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Gern, U.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, D-48149 Muenster, Germany.
    Schmid, R. M.
    2nd Department of Internal Medicine, University of Munich, D-81675 Munich, Germany.
    Röttinger, E. M.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Seufferlein, T.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappa B independent mechanisms2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 54, p. 8786-8796Article in journal (Refereed)
    Abstract [en]

    Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

  • 2.
    Belka, C.
    et al.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Marini, P.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Lepple-Wienhues, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Budach, W.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Jekle, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Lang, F.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Schulze-Osthoff, K.
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Gulbins, E.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Bamberg, M.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation1999In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 18, no 35, p. 4983-4992Article in journal (Refereed)
    Abstract [en]

    Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis, Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck, Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression, This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.

  • 3.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Ahnström Waltersson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Fornander, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Skoog, L
    Department of Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Nordenskjöld, Bo
    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.
    Stål, Olle
    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.
    Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.2007In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 49, p. 6997-7005Article in journal (Refereed)
    Abstract [en]

    The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

  • 4.
    Burek, C. J.
    et al.
    University of Münster, Germany.
    Roth, J.
    University of Münster, Germany.
    Koch, H. G.
    University of Münster, Germany.
    Harzer, K.
    University of Tübingen, Germany.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Germany.
    Schulze-Osthoff, Klaus
    University of Münster, Germany .
    The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells2001In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 45, p. 6493-6502Article in journal (Refereed)
    Abstract [en]

    The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis.

  • 5.
    Burek, M.
    et al.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Burek, C. J.
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Daniel, P. T.
    Department of Hematology, Oncology and Tumor Immunology, Charité, Berlin, Germany.
    Schulze-Osthoff, Klaus
    nstitute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent2006In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, no 15, p. 2213-2222Article in journal (Refereed)
    Abstract [en]

    Apoptin, a chicken anemia virus-derived protein, selectively induces apoptosis in transformed but not in normal cells, thus making it a promising candidate as a novel anticancer therapeutic. The mechanism of apoptin-induced apoptosis is largely unknown. Here, we report that contrary to previous assumptions, Bcl-2 and Bcl-x(L) inhibit apoptin-induced cell death in several tumor cell lines. In contrast, deficiency of Bax conferred resistance, whereas Bax expression sensitized cells to apoptin-induced death. Cell death induction by apoptin was associated with cytochrome c release from mitochondria as well as with caspase-3 and -7 activation. Benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad spectrum caspase inhibitor, was highly protective against apoptin-induced cell death. Apoptosis induced by apoptin required Apaf-1, as immortalized Apaf-1-deficient fibroblasts as well as tumor cells devoid of Apaf-1 were strongly protected. Thus, our data indicate that apoptin-induced apoptosis is not only Bcl-2- and caspase dependent, but also engages an Apaf-1 apoptosome-mediated mitochondrial death pathway.

  • 6.
    Gentile, Massimiliano
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Ahnström, Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Schön, Fredrik
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Candidate tumour suppressor genes at 11q23-q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis2001In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 20, no 53, p. 7753-7760Article in journal (Refereed)
    Abstract [en]

    One of the most consistently deleted chromosomal regions in solid tumours is 11q23-q25, which consequently has been postulated to harbour one or more tumour suppressor loci. Despite large efforts to identify the responsible genes, the goal remains elusive, but as knowledge accumulates new candidates are emerging. The present study was undertaken in an attempt to assess the possible implication of four genes residing at 11q23-q24, in a population of early onset breast cancer (n=41). The coding sequence of PIG8, CHK1, LOH11CR2A and PPP2R1B were screened for mutations using the protein truncation test or single-strand conformational polymorphism, in combination with direct DNA sequencing. Varying proportions of alterations were detected, ranging from 6% in PPP2R1B to 39% in PIG8. Many of these changes were deletions, in some cases corresponding to complete exons, thus likely to represent splice variants, while others were presumed to arise from aberrant splicing, since they occurred at sites with resemblance to exon/intron borders. Considering only bona fide mutations, the highest alteration frequency (17%) was again found in PIG8. Most of these alterations were likely to have an adverse impact on the translated protein as they either altered the reading frame or affected phylogenetically conserved residues. Our data represent the first evidence of alterations in the PIG8 gene in human malignancies, a finding that substantiates its role as a potential tumour suppressor gene as suggested by its involvement in p53-induced apoptosis. 

  • 7.
    Gunnarsson, Cecilia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Ahnström, Marie
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Kirschner, Kristina
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Rutqvist, Lars Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Amplification of HSD17B1 and ERBB2 in primary breast cancer2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 1, p. 34-40Article in journal (Refereed)
    Abstract [en]

    Estrogens play a crucial role in the development of breast cancer. Estradiol can be produced in the breast tissue in situ, and one of the enzymes involved in this process is 17β-hydroxysteriod dehydrogenase (17β-HSD) type 1 that catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (HSD17B1) is located at 17q12-21, close to the more studied ERBB2 and BRCA1. The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer. We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2. In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2. Amplification of the two genes was correlated (P = 0.00078) and in 14 tumors (44%) with amplification of HSD17B1, ERBB2 was co amplified. The patients with amplification in at least one of the genes had a significantly worse outcome than patients without (P = 0.0059). For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P = 0.017), whereas amplification of ERRB2 was not. Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment.

  • 8.
    Gómez-Maldonado, L
    et al.
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain, .
    Tiana, M
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
    Roche, O
    IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain, IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
    Prado-Cabrero, A
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Fernandez-Barral, A
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
    Guijarro-Muñoz, I
    Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
    Favaro, E
    Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
    Moreno-Bueno, G
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
    Sanz, L
    Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
    Aragones, J
    Research Unit, Hospital Universitario Santa Cristina, Research Institute Princesa, Autonomous University of Madrid, Madrid, Spain.
    Harris, A
    Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
    Volpert, O
    Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    Jimenez, B
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
    Del Peso, L
    Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain, IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
    EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.2015In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, no 20, p. 2609-2620Article in journal (Refereed)
    Abstract [en]

    The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.Oncogene advance online publication, 14 July 2014; doi:10.1038/onc.2014.200.

  • 9.
    Hirai, S.
    et al.
    Yokohama City University School of Medicine, Japan.
    Izawa, M.
    Yokohama City University School of Medicine, Japan.
    Osada, S.
    Yokohama City University School of Medicine, Japan.
    Spyrou, Giannis
    Karolinska Institute, Stockholm, Sweden.
    Ohno, S.
    Yokohama City University School of Medicine, Japan.
    Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK1996In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 12, no 3, p. 641-650Article in journal (Refereed)
    Abstract [en]

    JNK/SAPKs are identified as new members of the MAPK family; they phosphorylate c-Jun protein in response to several cellular stimuli including ultraviolet irradiation, TNF and osmotic shock. We have identified a protein kinase, MUK, as an activator of the JNK-pathway, whose kinase domain shows significant homology to MAPKKK-related proteins such as c-Raf and MEKK. The over-expression of MUK or MEK kinase (MEKK) in NIH3T3 or COS1 cells results in the activation of JNK1 and the accumulation of a hyper-phosphorylated form of c-Jun. While MEKK also activates the ERK pathway, MUK is a rather selective activator of the JNK pathway. On the other hand, c-Raf activates the JNK pathway only slightly despite its remarkable ability to activate the ERK pathway. Even though we originally identified MUK as a MAPKKK-related protein kinase, a greater similarity to mixed lineage kinase (MLK) is found not only in the catalytic domain but also in the 'leucine-zipper'-like motifs located at the C-terminal side of the catalytic domain. The structural divergence between MUK and MEKK reveals the multiplicity of signaling pathways that activate JNK/SAPKs.

  • 10.
    Jansson, Agneta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Emterling, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Arbman, Gunnar
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Noxa in colorectal cancer: A study on DNA, mRNA and protein expression2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 30, p. 4675-4678Article in journal (Refereed)
    Abstract [en]

    Noxa is a BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage. Mutations in the BH3-only region of other BH3-only members lead to an inactive protein. We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa. Among them, Noxa protein expression was investigated with immunohistochemistry in 16 tumors and six corresponding normal mucosa samples. Further, we searched for Noxa mutations in all the cases using single-stranded conformation polymorphism and DNA sequencing. The mRNA expression of Noxa was weak in 9% and strong in 2% of the tumors, and decreased in 9% and increased in 16% of the tumors compared with the normal mucosa, however, these changes did not have any clinical or pathological significance. The protein level in most of the cases investigated was correlated with the mRNA level. We did not find any mutations in the Noxa gene. Thus, we suggest that Noxa may not be of importance in the development of colorectal cancer.

  • 11. Johnsen, J I
    et al.
    Segerstrom, L
    Orrego, A
    Elfman, L
    Henriksson, M
    Kågedal, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Eksborg, S
    Sveinbjornsson, B
    Kogner, P
    Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 20, p. 2910-2922Article in journal (Refereed)
    Abstract [en]

    Mammalian target of rapamycin (mTOR) has been shown to play an important function in cell proliferation, metabolism and tumorigenesis, and proteins that regulate signaling through mTOR are frequently altered in human cancers. In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis. Significant expression of activated AKT and mTOR were detected in all primary neuroblastoma tissue samples investigated, but not in non-malignant adrenal medullas. mTOR inhibitors showed antiproliferative effects on neuroblastoma cells in vitro. Neuroblastoma cell lines expressing high levels of MYCN were significantly more sensitive to mTOR inhibitors compared to cell lines expressing low MYCN levels. Established neuroblastoma tumors treated with mTOR inhibitors in vivo showed increased apoptosis, decreased proliferation and inhibition of angiogenesis. Importantly, mTOR inhibitors induced downregulation of vascular endothelial growth factor A (VEGF-A) secretion, cyclin D1 and MYCN protein expression in vitro and in vivo. Our data suggest that mTOR inhibitors have therapeutic efficacy on aggressive MYCN amplified neuroblastomas. © 2008 Nature Publishing Group All rights reserved.

  • 12.
    Keklikoglou, I.
    et al.
    German Cancer Research Centre, Germany; Swiss Federal Institute Technology Lausanne EPFL, Switzerland.
    Hosaka, K.
    Karolinska Institute, Sweden.
    Bender, C.
    German Cancer Research Centre, Germany.
    Bott, A.
    German Cancer Research Centre, Germany.
    Koerner, C.
    German Cancer Research Centre, Germany.
    Mitra, D.
    German Cancer Research Centre, Germany.
    Will, R.
    German Cancer Research Centre, Germany.
    Woerner, A.
    German Cancer Research Centre, Germany.
    Muenstermann, E.
    German Cancer Research Centre, Germany.
    Wilhelm, H.
    German Cancer Research Centre, Germany.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Wiemann, S.
    German Cancer Research Centre, Germany.
    MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes2015In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, no 37, p. 4867-4878Article in journal (Refereed)
    Abstract [en]

    Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-kappa B transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-kappa B-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.

  • 13.
    Lacoste, Sandrine
    et al.
    University of Manitoba, Winnipeg, Canada.
    Wiechec, Emilia
    University of Aarhus, Denmark.
    Dos Santos Silva, Amanda
    Unversity of Sao Paulo, Brazil.
    Guffei, Amanda
    University of Manitoba, Winnipeg, Canada.
    Williams, G
    Lowbeer, M
    Benedek, K
    Henriksson, M
    Klein, George
    Mai, Sabine
    University of Manitoba, Winnipeg, Canada.
    Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cellsEBV infection-mediated genomic instability in B cells2010In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 29, p. 503-515Article in journal (Refereed)
    Abstract [en]

    The Epstein–Barr virus (EBV) is carried by more than 90% of the adult world population and has been implicated in several human malignancies. Its ability to induce unlimited in vitro proliferation of B cells is frequently used to generate lymphoblastoid cell lines (LCLs). In this study, we have investigated the evolution of two LCLs up to 25 weeks after EBV infection. LCLs were karyotyped once a month by spectral karyotyping (SKY). LCLs but not mitogen-activated B cells showed evidence of DNA damage and DNA damage response within the first 2 weeks. After 4 weeks, the former, but not the latter, showed a high level of non-clonal structural aberrations, mainly deletions, fragments, dicentric chromosomes and unbalanced translocations. Genomic instability decreased thereafter over time. Nonrandom aneuploidy 12 weeks after infection showed clonal evolution in culture. After 25 weeks post-infection, most cells exhibited karyotypic stability. Chromosomal aberrations were compatible with telomere dysfunction, although in the absence of telomere shortening. The telomere capping protein TRF2 was partially displaced from telomeres in EBV-infected cells, suggesting an EBV-mediated uncapping problem. In conclusion, this study suggests that DNA damage and telomere dysfunction contribute to EBV-related chromosomal instability in early LCLs.

  • 14.
    Lallemand, D.
    et al.
    Institut Pasteur, Paris cedex 15, France.
    Spyrou, Giannis
    Novum, Karolinska Institute, Huddinge, Sweden.
    Yaniv, M.
    Institut Pasteur, Paris cedex 15, France.
    Pfarr, C. M.
    Institut Pasteur, Paris cedex 15, France.
    Variations in Jun and Fos protein expression and AP-1 activity in cycling, resting and stimulated fibroblasts1997In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 14, no 7, p. 819-830Article in journal (Refereed)
    Abstract [en]

    We have analysed the different Jun and Fos proteins as NIH3T3 fibroblasts pass from exponential growth to quiescence and during the first 24 h after their re-entry into the cell cycle following serum stimulation. We show that these proteins can be divided into 3 subgroups based on their pattern of expression. The first contains c-Jun, Jun-D and Fra-2 which are expressed at high level in cycling cells and are only mildly induced by serum. The second contains Jun-B, c-Fos, Fos-B and deltaFos-B whose levels are low in cycling cells but increase strongly and rapidly after stimulation by serum. The third group contains only Fra-1, which is absent from cycling cells and behaves as a delayed early response protein after serum stimulation. AP-1 binding activity is low both in cycling and quiescent fibroblasts but increases after stimulation by serum with kinetics matching the induction of the various Jun and Fos proteins. Antibody supershift analyses demonstrate that the composition of AP-1 binding activity reflects the relative abundance of each Jun and Fos protein. Furthermore, the state of post-translational modification varies continuously for all of the AP-1 proteins as growth conditions change. These data indicate that AP-1 activity during the G0-G1 transition is finely regulated and complex, involving changes both in protein expression and in posttranslational modification.

  • 15.
    Maddika, Subbareddy
    et al.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    Ande, S. R.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
    Poon, I. K.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Fischer, Ute
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and BioApplications Enterprises, Winnipeg, Manitoba, Canada.
    Jans, D. A.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
    Interaction with PI3-kinase contributes to the cytotoxic activity of Apoptin2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, p. 3060-3065Article in journal (Refereed)
    Abstract [en]

    Apoptin, a small protein from the chicken anemia virus, has attracted attention because of its specificity in killing tumor cells. Localization of apoptin in the nucleus of tumor cells has been shown to be vital for proapoptotic activity, however, targeted expression of apoptin in the nucleus of normal cells does not harm the cells, indicating that nuclear localization of apoptin is insufficient for its cytotoxicity. Here, we demonstrate for the first time that apoptin interacts with the SH3 domain of p85, the regulatory subunit of phosphoinositide 3-kinase (PI3-K), through its proline-rich region. Apoptin derivatives devoid of this proline-rich region do not interact with p85, are unable to activate PI3-K, and show impaired apoptosis induction. Moreover, apoptin mutants containing the proline-rich domain are sufficient to elevate PI3-K activity and to induce apoptosis in cancer cells. Downregulation of p85 leads to nuclear exclusion of apoptin and impairs cell death induction, indicating that interaction with the p85 PI3-K subunit essentially contributes to the cytotoxic activity of apoptin.

  • 16.
    Singleton, D. C.
    et al.
    University of Oxford, England.
    Rouhi, P.
    Karolinska Institute, Sweden.
    Zois, C. E.
    University of Oxford, England.
    Haider, S.
    University of Oxford, England.
    Li, J-L
    University of Oxford, England.
    Kessler, B. M.
    University of Oxford, England.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Harris, A. L.
    University of Oxford, England.
    Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis2015In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, no 36, p. 4713-4722Article in journal (Refereed)
    Abstract [en]

    Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1 alpha (HIF1 alpha) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1 alpha-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.

  • 17.
    Staffas, A.
    et al.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Arabanian, L. S.
    University of Gothenburg, Sweden.
    Wei, S. Y.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Jansson, A.
    Sahlgrens University Hospital, Sweden.
    Stahlman, S.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Johansson, P.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Fogelstrand, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Kuchenbauer, F.
    University Hospital Ulm, Germany.
    Palmqvist, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice2017In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 11, p. 1516-1524Article in journal (Refereed)
    Abstract [en]

    HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL -/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL -/- mice as rapid as in wild-type mice. However, FL -/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3 dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1.

  • 18.
    Xu, DW
    et al.
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Wang, Q
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Gruber, A
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Bjorkholm, M
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Chen, ZG
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Zaid, A
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Selivanova, G
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Peterson, C
    Wiman, KG
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Pisa, P
    Karolinska Hosp, Hematol Lab, CMM, Radiumhemmet,Dept Med,Div Hematol, SE-17176 Stockholm, Sweden Karolinska Hosp, Radiumhemmet, Dept Oncol, SE-17176 Stockholm, Sweden Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden Stockholm Univ, Dept Biochem, SE-10405 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, SE-58185 Linkoping, Sweden.
    Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells2000In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 19, no 45, p. 5123-5133Article in journal (Refereed)
    Abstract [en]

    The p53 tumor suppressor protein inhibits the formation of tumors through induction of cell cycle arrest and/or apoptosis, In the present study we demonstrated that p53 is also a powerful inhibitor of human telomerase reverse transcriptase (hTERT), a key component for telomerase, Activation of either exogenous temperature-sensitive (ts) p53 in BL41 Burkitt lymphoma cells or endogenous wild type (wt) p53 at a physiological level in MCF-7 breast carcinoma cells triggered a rapid downregulation of hTERT mRNA expression, independently of the induction of the p53 target gene p21, Co-transfection of an hTERT promoter construct with wt p53 but not mutant p53 in HeLa cells inhibited the hTERT promoter activity. Furthermore, the activation of the hTERT promoter in Drosophila Schneider SL2 cells was completely dependent on the ectopic expression of Sp1 and was abrogated by wt p53, Finally, wt p53 inhibited Sp1 binding to the hTERT proximal promoter by forming a p53-Sp1 complex. Since activation of telomerase, widely observed in human tumor cell lines and primary tumors, is a critical step in tumorigenesis, wt p53-triggered inhibition of hTERT/telomerase expression may reflect yet another mechanism of p53-mediated tumor suppression. Our findings provide new insights into both the biological function of p53 and the regulation of hTERT/telomerase expression.

  • 19.
    Zhuang, Shi-Mei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Wiseman, Roger W
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Frequent mutations of the Trp53,Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice2002In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 21, no 36, p. 5643-5648Article in journal (Refereed)
    Abstract [en]

    DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including ▀-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wildtype Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Aras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G?C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.

  • 20.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland.
    Cecconi, Virginia
    Univ Zurich, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Restivo, Gaetana
    Univ Hosp Zurich, Switzerland.
    Hafner, Jurg
    Univ Hosp Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    van den Broek, Maries
    Univ Zurich, Switzerland.
    WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 27, p. 3753-3762Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

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