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- Pizzolato, Giulia, 1990-
(författare)
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Molecular characterization of FOX factors and Wnt signalling interplay in human cancers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Wnt/β-catenin signalling, also referred to as canonical Wnt signalling, is a critical regulator of tissue homeostasis and of the differentiation of cells during development. The outcome of canonical Wnt pathway activity is defined by the regulation of target gene transcription, which ultimately determines cell identity and proliferation. How multiple proteins coordinate to modulate Wnt signalling in numerous tissues is an evolving question.Over the years, FOX transcription factors have been emerging as modulators of Wnt signalling in a variety of tissue and cell-specific contexts. Nevertheless, the function of each FOX protein in the pathway as well as their role in different pathophysiological contexts is an open matter.The overall aim of this thesis was to investigate two FOX family members, FOXB2 and FOXQ1, to uncover their roles in Wnt/β-catenin signalling. Additionally, in the last work, I aimed to investigate how the FOXQ1 oncogene is transcriptionally regulated in cancer.In the first paper, we uncovered FOXB2 as a new potent activator of Wnt signalling via the induction of agonistic Wnt ligands, particularly WNT7B. In addition, FOXB2 is induced in aggressive prostate cancer where it is associated with a neuroendocrine differentiation program and poor prognosis.In the second paper, we explored the molecular mechanisms used by the carcinoma oncogene FOXQ1 to drive Wnt signalling activation. Our results showed that FOXQ1 has a major role in tuning the Wnt transcriptional output and, in synergy with active Wnt signalling, converged on a transcriptional program linked to epithelial-to-mesenchymal transition (EMT) and cell migration, which has important implications for cancer biology.In the third paper, we reveal that p53 functions as transcriptional repressor of FOXQ1 in cancers. Loss of p53 is present in the majority of human cancers and, in synergy with activation of Wnt signalling, could boost FOXQ1 expression, thereby affecting the progression of cancer.Overall, this thesis provides a better understanding of the complexity of Wnt signalling on the molecular level and newly elucidates the function of these two FOX proteins as drivers of oncogenic Wnt pathway activation. Additionally, this new evidence highlights the importance of further in-depth investigation of FOX transcription factors in cancer biology. The relevant role of FOX proteins in the development and progression of cancer is increasingly evident, and in the long run, it will be valuable to characterize the role of FOX factors in a tissue-specific context for the development of targeted cancer therapies.
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