Epigenetic modification of the Wnt pathway mediated\ud by Brg1

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Holik, Aliaksei;
  • Subject: QH426

Colorectal cancer is one of the most clinically significant types of cancer due to both high incidence and mortality. Despite the well-established role of aberrant Wnt signalling in initiation and progression of colorectal cancer, therapies that specifically target the Wn... View more
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    311 references, page 1 of 32

    1.2.7.1 Constitutive transgenesis . . . . . . . . . . . . . . . . . . . 42 1.2.7.2 Conditional transgenesis . . . . . . . . . . . . . . . . . . . 42

    1.3 Brg1 as a therapeutic target candidate for Wnt-driven tumourigenesis . . . 44 1.3.1 Discovery and functional redundancy between paralogues . . . . . . 45 1.3.2 Physiological functions of BRG1 . . . . . . . . . . . . . . . . . . . . 46 1.3.2.1 BRG1 protein-protein interactions . . . . . . . . . . . . . 46 1.3.3 The role of BRG1 in mammalian development . . . . . . . . . . . . 46 1.3.4 The role of BRG1 as a tumour suppressor . . . . . . . . . . . . . . 47 1.3.5 BRG1 as a mediator of the Wnt pathway - the oncogenic face of BRG1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

    1.4 Aims and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.6.3 Western-blotting analysis . . . . . . . . . . . . . . . . . . . . . . . . 76

    2.7 Quantitative and statistical analysis of data . . . . . . . . . . . . . . . . . 78 2.7.1 Quantitative analysis of histological parameters . . . . . . . . . . . 78 2.7.2 Comparison of means . . . . . . . . . . . . . . . . . . . . . . . . . . 78 2.7.3 Comparison of medians . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.7.4 Kolmogorov-Smirnov Z test . . . . . . . . . . . . . . . . . . . . . . 79 2.7.5 Kaplan-Meier survival analysis . . . . . . . . . . . . . . . . . . . . . 80

    3.3.2 Complete Brg1 loss has mild immediate effects on intestinal homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

    3.3.3 Brg1 loss compromises the function of the small intestinal stem cell 112

    3.3.4 Brg1 haploinsufficiency does not induce intestinal tumourigenesis, but impairs the stem cell clonogenic capacity . . . . . . . . . . . . . 116

    3.3.5 Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 4.2.5.1 Brg1 deficient cells are retained in the bladder urothelium over a long period of time . . . . . . . . . . . . . . . . . . 138

    4.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 4.3.1 Brg1 haploinsufficiency has no overt oncogenic effect in a subset of tissues expressing AhCre recombinase . . . . . . . . . . . . . . . . . 139 4.3.2 Brg1 loss induces the development of benign tumours in epithelial tissues of the murine stomach . . . . . . . . . . . . . . . . . . . . . 140 4.3.3 Long-term Brg1 loss is tolerated in the large intestinal and bladder epithelial tissue and has no tumourigenic effect . . . . . . . . . . . 143 4.3.4 Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

    1.1 Histology of the small intestinal epithelium . . . . . . . . . . . . . . . . . . 4

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