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  • 1.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Inflammation-associated genes and genetic variations in colorectal cancer2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Colorectal cancer is a major cause of morbidity and mortality around the world, each year affecting about one million individuals worldwide. The disease is characterized by an accumulation of genetic alterations, and a sequence of events leading to the development of an invasive and metastasising tumour. Chronic or dysregulated inflammation may contribute to tumour initiation and progression via the release and activity of various mediators – e.g. cytokines, prostaglandins, inducible nitric oxide synthase (NOS2), matrix metalloproteinases (MMPs), and vascular endothelial growth factors (VEGF). In the present thesis, genes and genetic alterations controlling these events were analysed and discussed within the context of colorectal cancer.

    Prostaglandins, being generated from arachidonic acid in reactions dependent on cyclooxygenases (COX-1, COX-2), have been implicated in carcinogenesis of many organs. Since the quite recent characterization of the terminal and specific prostaglandin synthases, which act downstream of COX enzymes, the search for molecular targets which selectively suppress individual prostanoids has been intensified. In papers I-II, the role and regulation of inducible prostaglandin E2 (PGE2) synthase - mPGES-1 - were explored within the context of intestinal cancer. mPGES-1 was genetically deleted in the ApcMin/+ mouse - yielding marked suppression of PGE2 generation in intestinal and tumour tissue. However, a shift towards enhanced generation of non-PGE2 prostanoids was observed in mPGES-1 knock out mice, and these mice developed more and larger instestinal tumours. These results therefore indicate that targeting mPGES-1 may paradoxically promote tumourigenesis, most likely by secondary effects on other potentially pro-tumoural mediators. We also explored the relation of the commonly mutated APC gene and mPGES-1 in colon tumour cells, and found that high expression of mPGES-1 was associated with the presence of wild type APC. Rather than by regulating putative β-catenin/Tcf binding sites of the mPGES-1 promoter, APC seems to influence the stabilisation of mPGES-1 mRNA.

    In papers III-V, the possible contribution of variations in regulatory regions of genes encoding NOS2, MMPs, and VEGF, was assessed in populations of colorectal cancer patients and healthy control individuals. A single nucleotide insertion (1G/2G) at -1607 upstream the transcription start site of the MMP-1 gene was identified to be a susceptibility factor for colorectal cancer development, although no relation with disease characteristics was observed. Except for a rather uncommon combination of two individual polymorphisms of the VEGF gene, investigated genetic variations of VEGF, other MMPs, and NOS2, were not associated with colorectal cancer susceptibility or clinicopathological characteristics. We therefore suggest that other molecular events play more significant roles for the dysregulation of these genes in colorectal tumours.

    In summary, accumulating evidence, including the results here presented, suggest significant albeit complex roles of inflammation-induced genes and mediators in colorectal tumourigenesis. The present results may aid in identifying or excluding potential biomarkers and drug targets within cancer-related inflammation.

    List of papers
    1. Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice
    Open this publication in new window or tab >>Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice
    Show others...
    2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 372, no 1, p. 249-253Article in journal (Refereed) Published
    Abstract [en]

    The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.

    Keywords
    6-Ketoprostaglandin F1 alpha/analysis Animals Cell Transformation, Neoplastic/*genetics/pathology Colorectal Neoplasms/*genetics/pathology Dinoprostone/analysis/*metabolism Female *Gene Deletion Intramolecular Oxidoreductases/*genetics Male Mice Mice, Mut
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-43256 (URN)10.1016/j.bbrc.2008.05.026 (DOI)73147 (Local ID)73147 (Archive number)73147 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
    Open this publication in new window or tab >>Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
    Show others...
    2009 (English)In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 48, no 5, p. 401-407Article in journal (Refereed) Published
    Abstract [en]

    Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H-2 (PGH(2)), in particular prostaglandin E-2 (PGE(2)), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH(2) into PGE(2). Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGFS-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.

    Keywords
    cyclooxygenase 2, Prostaglandin E-2, beta-catenin, adenomatosis polyposis coli (APC), microsomal prostaglandin E synthase-1 (mPGES-1), colorectal cancer
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18549 (URN)10.1002/mc.20500 (DOI)
    Available from: 2009-06-01 Created: 2009-06-01 Last updated: 2017-12-13Bibliographically approved
    3. Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
    Open this publication in new window or tab >>Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
    2005 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 225, no 1, p. 99-103Article in journal (Refereed) Published
    Abstract [en]

    Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-30426 (URN)10.1016/j.canlet.2005.02.006 (DOI)15988 (Local ID)15988 (Archive number)15988 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
    4. Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
    Open this publication in new window or tab >>Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
    2006 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 1 B, p. 791-795Article in journal (Refereed) Published
    Abstract [en]

    Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC). Materials and Methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP. Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations. Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37785 (URN)38605 (Local ID)38605 (Archive number)38605 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    5. Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population
    Open this publication in new window or tab >>Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population
    2009 (English)In: MOLECULAR MEDICINE REPORTS, ISSN 1791-2997, Vol. 2, no 3, p. 435-439Article in journal (Refereed) Published
    Abstract [en]

    Vascular endothelial growth factor (VEGF) plays a significant role in tumor angiogenesis and is found to be overexpressed and involved in the development and progression of colorectal cancer (CRC). The VEGF gene contains several polymorphic sites known to influence VEGF expression. We examined the possible association between five polymorphisms, located in the promoter/5-untranslated region [-2578 (C/A), -2549 (del/ins 18 bp) -1154 (G/A), -634 (G/C)] or 3-untranslated region [+936 (C/T)] of the VEGF gene, and CRC Susceptibility and clinicopathological characteristics in 302 Swedish CRC patients and 336 healthy randomly selected controls. Both genotypes and combined haplotypes were analyzed. No significant differences were observed when VEGF genotype/haplotype frequencies in the CRC cases and controls were compared, nor were any associations found between the genotypes/haplotypes and clinicopathological characteristics. However, when the -2578 C and +936 T alleles were combined, a small but significant association with CRC susceptibility was detected (OR=1.6, 95% CI 1.3-1.9, p=0.01). In addition, VEGF mRNA expression was determined in a Subset of patients, revealing a 2-fold VEGF upregulation in CRC tissue compared to normal colonic mucosa, but no association between the genotypes or haplotypes and VEGF mRNA levels. Linkage analysis was performed, revealing that the polymorphisms in the promoter and 5-untranslated region were in tight linkage disequilibrium (LD) (vertical bar Dvertical bar=0.91-1.00), while the +936 C/T polymorphism was only weakly associated with the others (vertical bar Dvertical bar=0.05-0.19). In conclusion, VEGF is generally upregulated in colorectal tumors. However, the single nucleotide polymorphisms examined do not appear to influence the mRNA expression of VEGF in colorectal tumors, and most likely play a limited role in CRC development and progression.

    Keywords
    vascular endothelial growth factor, colorectal cancer, mRNA, single nucleotide polymorphism, haplotype analysis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18021 (URN)10.3892/mmr_00000118 (DOI)
    Available from: 2009-05-04 Created: 2009-05-04 Last updated: 2014-09-11
  • 2.
    Elander, Nils
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Fransén, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 1 B, p. 791-795Article in journal (Refereed)
    Abstract [en]

    Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC). Materials and Methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP. Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations. Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.

  • 3.
    Elander, Nils
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Uematsu, Satoshi
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Akira, Shizuo
    Department of Host Defense, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 372, no 1, p. 249-253Article in journal (Refereed)
    Abstract [en]

    The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.

  • 4.
    Elander, Nils
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Zhou, Jianlin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dimberg, Jan
    Jönköping University.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer2009In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 48, no 5, p. 401-407Article in journal (Refereed)
    Abstract [en]

    Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H-2 (PGH(2)), in particular prostaglandin E-2 (PGE(2)), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH(2) into PGE(2). Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGFS-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.

  • 5.
    Ellegård, Sander
    et al.
    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 Oncology.
    Veenstra, Cynthia
    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 Oncology.
    Pérez-Tenorio, Gizeh
    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 Oncology.
    Fagerström, Victor
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Department of Surgery, Kalmar Hospital, Kalmar.
    Garsjo, Jon
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Gert, Krista
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sundquist, Marie
    Department of Surgery, Kalmar Hospital, Kalmar.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Wingren, Sten
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Elander, Nils
    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 Oncology.
    Hallbeck, Anna-Lotta
    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 Oncology.
    Stål, Olle
    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 Oncology.
    ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab2019In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, no 3, p. 3371-3381Article in journal (Refereed)
    Abstract [en]

    Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

  • 6.
    Fransén, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    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.
    Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer2005In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 225, no 1, p. 99-103Article in journal (Refereed)
    Abstract [en]

    Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.

  • 7.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Belenki, Dimitri
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jawad Ul-Hassan, Aksa
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Work and Environmental Science. Linköping University, Faculty of Health Sciences.
    Fransén, Karin
    Department of Clinical Medicine, School of Health and Medical Science, Örebro University, Sweden.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 11, p. 2126-2134Article in journal (Refereed)
    Abstract [en]

    Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

  • 8.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Belenki, Dimitri
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jawad ul-Hassan, Aksa
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Franzén, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variation in NFκB signaling pathway genes in colorectal cancer susceptibility and survivalManuscript (preprint) (Other academic)
    Abstract [en]

    PURPOSE: Variations in genes orchestrating inflammatory responses,  such as those being connected with NFκB and NLRP3 inflammasome signaling, are associated with chronic inflammatory bowel diseases, which are well-known risk factors for colorectal cancer (CRC). The purpose of this study was to investigate the association between genetic variation and alterations in genes involved in NFκB and NLRP3 inflammasome signaling and their possible influence on susceptibility and clinical outcome of colorectal cancer.

    EXPERIMENTAL DESIGN: 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB, TNFAIP3, NLRP3, CARD8 and TLR4 genes. Chi-square tests and multiple logistic regression analysis were used to test for associations between the SNPs and CRC susceptibility, while log-rank tests and Cox proportional hazard regression analysis were used to examine the association between the SNPs and CRC-specific survival. Gene expression assay and loss of heterozygosity analyzes of TNFAIP3 were carried out in a subset of tumors to assess its role as a potential tumor suppressor in CRC.

    RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NFκB -94 ATTG ins/del and heterozygous NLRP3 (Q705K) genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2 95% CI 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared to adjacent non-neoplastic mucosa (P < 0.0001) and LOH of 6q23.3, (TNFAIP3), was detected in 17% of cases, while only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations.

    CONCLUSIONS: A panel of the TNFAIP3 (rs6920220), NFκB -94 ATTG ins/del and NLRP3 (Q705K) polymorphisms are associated with poor survival in patients with advanced CRC and may be used as a prognostic marker. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

  • 9.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dimberg, Jan
    Jönköping University.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population2009In: MOLECULAR MEDICINE REPORTS, ISSN 1791-2997, Vol. 2, no 3, p. 435-439Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) plays a significant role in tumor angiogenesis and is found to be overexpressed and involved in the development and progression of colorectal cancer (CRC). The VEGF gene contains several polymorphic sites known to influence VEGF expression. We examined the possible association between five polymorphisms, located in the promoter/5-untranslated region [-2578 (C/A), -2549 (del/ins 18 bp) -1154 (G/A), -634 (G/C)] or 3-untranslated region [+936 (C/T)] of the VEGF gene, and CRC Susceptibility and clinicopathological characteristics in 302 Swedish CRC patients and 336 healthy randomly selected controls. Both genotypes and combined haplotypes were analyzed. No significant differences were observed when VEGF genotype/haplotype frequencies in the CRC cases and controls were compared, nor were any associations found between the genotypes/haplotypes and clinicopathological characteristics. However, when the -2578 C and +936 T alleles were combined, a small but significant association with CRC susceptibility was detected (OR=1.6, 95% CI 1.3-1.9, p=0.01). In addition, VEGF mRNA expression was determined in a Subset of patients, revealing a 2-fold VEGF upregulation in CRC tissue compared to normal colonic mucosa, but no association between the genotypes or haplotypes and VEGF mRNA levels. Linkage analysis was performed, revealing that the polymorphisms in the promoter and 5-untranslated region were in tight linkage disequilibrium (LD) (vertical bar Dvertical bar=0.91-1.00), while the +936 C/T polymorphism was only weakly associated with the others (vertical bar Dvertical bar=0.05-0.19). In conclusion, VEGF is generally upregulated in colorectal tumors. However, the single nucleotide polymorphisms examined do not appear to influence the mRNA expression of VEGF in colorectal tumors, and most likely play a limited role in CRC development and progression.

  • 10.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grunberg, John
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Studies on potential Wnt/beta-catenin- target genes in the Notch signalling pathway with special emphasis on colorectal cancer in INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol 24, issue , pp S26-S262009In: INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2009, Vol. 24, p. S26-S26Conference paper (Refereed)
    Abstract [en]

    n/a

  • 11.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grunberg, John
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    The Notch-2 Gene Is Regulated by Wnt Signaling in Cultured Colorectal Cancer Cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. 0017957-Article in journal (Refereed)
    Abstract [en]

    Background: Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways may lead to the development of colorectal cancer (CRC). In CRC the Apc/beta-catenin genes in the Wnt signaling pathway are frequently mutated and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has previously been suggested in normal development as well as in cancer. Principal Findings: In this study, in silico analysis of putative promoters involved in transcriptional regulation of genes coding for proteins in the Notch signaling pathway revealed several putative LEF-1/TCF sites as potential targets for beta-catenin and canonical Wnt signaling. Further results from competitive electrophoretic mobility-shift assay (EMSA) studies suggest binding of several putative sites in Notch pathway gene promoters to in vitro translated beta-catenin/Lef-1. Wild type (wt)-Apc negatively regulates beta-catenin. By induction of wt-Apc or beta-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Finally, active Notch signaling was verified in the Apc(Min/+) mouse model where Hes-1 mRNA levels were found significantly upregulated in intestinal tumors compared to normal intestinal mucosa. Luciferase assays showed an increased activity for the core and proximal Notch-2 promoter upon co-transfection of HCT116 cells with high expression recombinant Tcf-4, Lef-1 or beta-catenin. Conclusions: In this paper, we identified Notch-2 as a novel target for beta-catenin-dependent Wnt signaling. Furthermore our data supports the notion that additional genes in the Notch pathway might be transcriptionally regulated by Wnt signaling in colorectal cancer.

  • 12.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grünberg, John
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Notch-2 and the Notch signaling pathway are regulated by Wnt signaling in colorectal cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Both Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways can lead to development of colorectal cancer, where the Apc/β-catenin-genes in the Wnt signaling pathway are frequently mutated, and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has been indicated.

    Using bioinformatics, we identified and screened proximal Notch pathway gene promoters for putative TCF/LEF1 sites, targets for β-catenin. Wild type (wt)-Apc negatively regulates β-catenin and by using semi-quantitative PCR, induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Electrophoretic mobility-shift assay (EMSA) confirmed binding of Lef-1 to Notch-2 as well as other Notch pathway gene promoters and luciferase assays showed an increased activity for the LEF1/TCF-site at position -110 in the Notch-2 promoter upon cotransfection of HT29 or HCT116 cells with mutated β-catenin. Taken together, these results indicate that activation of the Wnt pathway with increased levels of β-catenin can function as a transcriptional regulator of the Notch pathway in colon cancer cell lines.

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