The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis:
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| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2013
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| Schlagworte: | |
| Online-Zugang: | kostenfrei https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 Inhaltsverzeichnis |
| Beschreibung: | 147 Bl. Ill., graph. Darst. |
Internformat
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| 100 | 1 | |a Schwitalla, Sarah |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |c Sarah Schwitalla |
| 264 | 1 | |c 2013 | |
| 300 | |a 147 Bl. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |a München, Techn. Univ., Diss., 2013 | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
| 776 | 0 | 8 | |i Erscheint auch als |n Online-Ausgabe |o urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 |
| 856 | 4 | 1 | |u http://mediatum.ub.tum.de/node?id=1114677 |x Verlag |z kostenfrei |3 Volltext |
| 856 | 4 | |u https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 |x Resolving-System | |
| 856 | 4 | 2 | |m DNB Datenaustausch |q application/pdf |u http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026018701&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |3 Inhaltsverzeichnis |
| 912 | |a ebook | ||
| 999 | |a oai:aleph.bib-bvb.de:BVB01-026018701 | ||
Datensatz im Suchindex
| _version_ | 1804150402333016064 |
|---|---|
| adam_text | IMAGE 1
TABLE OF CONTENTS
1. INTRODUCTION 5
1.1 EPIDEMIOLOGY OF COLORECTAL CARCINOGENESIS 5
1.2 A MODEL FOR COLORECTAL CARCINOGENESIS (FEARON & VOGELSTEIN MODEL) 5
1.3 INTESTINAL ARCHITECTURE & INTESTINAL STEM CELLS 7
1.4 30 YEARS OF WNT 10
1.5 WNT SIGNALING IN CANCER 12
1.6 CELL-OF-ORIGIN THEORY. 14
1.7 CANCER STEM CELLS 15
1.8 TUMOR PROGRESSION 17
1.9 TUMOR MICROENVIRONMENT THE 7TH HALLMARK OF CANCER 20
1.10 NF-KB 25
1.11 NF-KB IN CANCER 27
1.12 P53 29
OBJECTIVE OF THIS WORK 31
2. MATERIAL & METHODS 32
2.1 MICE - 32
2.1.1 MOUSE MODELS 32
2.1.2 GENOTYPING 35
2.1.3 AOM ADMINISTRATION 39
2.1.4 TAMOXIFEN ADMINISTRATION 39
2.1.5 BONE MARROW TRANSPLANTATION 39
2.1.6 FITC-DEXTRAN INTESTINAL PERMEABILITY TEST 40
2.1.7 DEPLETION OF INTESTINAL MICROFLORA 40
2.1.8 MINI ENDOSCOPY AND CONFOCAL LASER SCANNING MICROSCOPY (CLSM) 40
2.1.9 SACRIFICE OF MICE 41
2.1.10 INTESTINAL EPITHELIAL CELL ISOLATION 41
2.1.11 VILLUS ISOLATION AND PROPAGATION 41
2.1.12 ORGANOID CULTURE 42
2.1.13 BACTERIAL ENDOTOXIN TEST 42
2.2 HUMAN SAMPLES 43
2.3 HISTOLOGY.... :. 43
2.3.1 HAEMATOXYLIN & EOSIN IH&E) STAINING 43
2.3.2 ALCIAN BLUE STAINING 43
2.3.3 AZURE EOSIN STAINING 44
2.3.4 ALKALINE PHOSPHATASE STAINING 44
2.3.5 DUOLINK PROXIMITY LIGATION ASSAY 44
2.3.6 FLUORESCENCE IN SITU HYBRIDIZATION (FISHJ 45
2.3.7 IMMUNOHISTOCHEMICAL ANALYSIS 45
2.3.8 DIGOXIGENIN-LABELING OF IN SITU HYBRIDIZATION PROBES 46
2.3.9 IN SITU HYBRIDIZATION 47
2.3.10 TUNEL STAINING 49
2.3.11 TISSUE HYPOXIA DETECTION 50
2.4 RNA/DNA ANALYSIS 50
2.4.1 UNA ISOLATION SO
2.4.2 CDNA SYNTHESIS 51
2.4.3 REAL-TIME PCR ANALYSIS SI
2.4.4 MICROARRAY S3
2.4.5 DNA ISOLATION S4
2.4.6 ARRAY COMPARATIVE GENOMIC HYBRIDIZATION 54
2
HTTP://D-NB.INFO/1041768575
IMAGE 2
2.5 CLONING 54
2.5.1 CLONING OF THE CREER* SEQUENCE INTO THE ER STRESS INDICATOR (ERAI)
PLASMID 54 2.5.2 LIGATION OF A LINKER OLIGONUCLEOTIDE INTO A VECTOR
CONSTRUCT 56
2.5.3 LIGATION 56
2.5.4 TRANSFORMATION 56
2.5.5 ISOLATION OF PLASMID DNA FROM BACTERIA 57
2.6 CHROMATIN IMMUNOPRECIPITATION ANALYSIS (CHIP) 57
2.6.1 SEQUENTIAL CHIP (RE-CHIP) 58
2.7 PROTEIN ANALYSIS 58
2.7.1 PREPARATION OF PROTEIN LYSATES 58
2.7.2 WESTERN BLOT ANALYSIS 59
2.7.3 DNA AFFINITY PRECIPITATION ASSAY (DAPA) 62
2.7.4 EMSA (IR^PI ATP RADIOACTIVELY LABELED OLIGONUCLEOTIDE) 63
2.7.5 EMSA (3 DY682 INFRARED MARKER LABELED OLIGONUCLEOTIDE) 64
2.7.6 KINASE ASSAY 64
2.8 CELL CULTURE 65
2.8.1 CULTIVATION 65
2.8.2 TRANSFECTION 65
2.8.3 SIRNA MEDIATED KNOCKDOWN 66
2.8.4 LUCIFERASE ASSAY 66
2.9 STATISTICS 66
3. RESULTS 67
3.1 THE ROLE OF NF-KB DURING TUMOR INITIATION 67
3.1.1 MASSIVE CRYPT COMPARTMENT EXPANSION AND HYPERPROLIFERATION OF
INTESTINAL EPITHELIAL CELLS UPON CONSTITUTIVE FI-CATENIN ACTIVATION
PROMOTED BY TNF-A DEPENDENT NFKB ACTIVITY 67
3.1.2 NF-KB TRIGGERS THE INITIATION OF ADENOMATOUS CELL TRANSFORMATION
BY MODULATING WNT-DEPENDENT INTESTINAL STEIN CELL GENE EXPRESSION 69
3.1.3 ENHANCED NF-KB ACTIVITY ACCELERATES ABERRANT WNT
SIGNALING-DEPENDENT CRYPT STEM CELL HYPERPROLIFERATION AND INDUCES
DE-DIFFERENTIATION IN NON-STEM CELLS 74 3.1.4 EX VIVO DEDIFFERENTIATED
EPITHELIAL VILLUS CELLS FORM SPHEROIDS WITH TUMOR STEM CELL CAPABILITY.
76
3.1.5 RECOMBINATION IN DIFFERENTIATED ENTEROCYTES LEADS TO
DE-DIFFERENTIATION AND ADENOMA FORMATION IN VIVO 79
3.2 THE ROLE OF NF-KB DURING TUMOR PROGRESSION 84
3.2.1 LOSS OF P53 REQUIRES ADDITIONAL GENETIC MUTATION OF CTNNB IN ORDER
TO INDUCE TUMOR FORMATION AND INVASION 84
3.2.2 P53 REDUCES THE TUMOR INCIDENCE IN WNT- DEPENDENT TUMORIGENESIS BY
INDUCING APOPTOSIS AND A DNA DAMAGE PROGRAM IN AFFECTED CELLS 87
3.2.3 LOSS OFTP53 LEADS TO A MYELOID CELL DOMINATED INFLAMMATORY
MICROENVIRONMENT ASSOCIATED WITH NF-KB ACTIVATION FACILITATING EMT AND
INVASION 89
3.2.4 LOSS OF P53 LEADS TO INTESTINAL BARRIER DEFECT AFTER CARCINOGEN
EXPOSITION RESULTING IN INCREASED BACTERIAL TRANSLOCATION ANDSENIM LPS
LEVELS ACTIVATING NF-KB IN IEC 95 3.2.5 IKKFT-DEPENDENT NF-KB ACTIVATION
GENERATES A MYELOID DERIVED INFLAMMATORY MICROENVIRONMENT DRIVING EMT
AND PROMOTES AGGRESSIVE TUMOR INVASION AND METASTATIC
SPREAD THOUGH EPITHELIAL STAT3 ACTIVATION 99
3.2.6 TP53 ICMICE PROVIDE A FEASIBLE SYSTEM FOR PRE-CLINICAL
EXAMINATIONS. 105
4. DISCUSSION 107
4.1 NF-KB CAN BE ACTIVATED BY DIVERSE MECHANISMS AND IN TURN MODULATES
WNT SIGNALING BY DIRECT CROSSTALK WITH P-CATENIN DURING TUMOR INITIATION
107
4.2 NF-KB PATRONIZES CELL TYPE PLASTICITY DURING TUMOR INITIATION AND
DURING TUMOR PROGRESSION 109
3
IMAGE 3
4.3 INDIRECT INVERSE CROSSTALK BETWEEN NF-KB AND P53 FUNCTION REVEALS
DIFFERING TISSUE
SPECIFIC TUMOR SUPPRESSIVE ROLES OF P53 DURING TUMOR INITIATION AND
TUMOR PROGRESSION 113
4.4 INTESTINAL MICROBIATA HAS A UNIQUE TISSUE SPECIFIC TUMOR PROMOTING
ROLE. 115 4.5 THE TP53 ,EC MOUSE MODEL REPRESENTS THE HUMAN COURSE OF
COLORECTAL CANCER AND IS A SUITABLE MODEL FOR PRE-CLINICAL STUDIES 116
SUMMARY 119
CITATION INDEX 121
ABBREVIATIONS 139
CURRICULUM VITAE 142
PUBLICATIONS 144
DANKSAGUNG 146
4
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| spelling | Schwitalla, Sarah Verfasser aut The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis Sarah Schwitalla 2013 147 Bl. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Techn. Univ., Diss., 2013 (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 http://mediatum.ub.tum.de/node?id=1114677 Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026018701&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Schwitalla, Sarah The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |
| subject_GND | (DE-588)4113937-9 |
| title | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |
| title_auth | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |
| title_exact_search | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |
| title_full | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis Sarah Schwitalla |
| title_fullStr | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis Sarah Schwitalla |
| title_full_unstemmed | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis Sarah Schwitalla |
| title_short | The role of IKKbeta-dependent NF-kappaB signaling on different stages of intestinal carcinogenesis |
| title_sort | the role of ikkbeta dependent nf kappab signaling on different stages of intestinal carcinogenesis |
| topic_facet | Hochschulschrift |
| url | http://mediatum.ub.tum.de/node?id=1114677 https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20130307-1114677-0-6 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026018701&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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