The Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasis
Date
2020-06-05
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Abstract
Alternative splicing of mRNA in a mammalian cell allows generation of complexity in the proteome. The consequences of splicing and its biological significance is poorly understood in development and disease conditions. The research described in thesis investigates the biological significance of alternative splicing of the pre-mRNA of the transcription factor Transcription Factor-7 Like-2 (TCF7L2) into the three major E, S and M isoforms in epithelial and carcinoma cells. Epithelial-mesenchymal transition (EMT) is a fundamental process in development and contributes to pathological conditions including cancer. EMT contributes to cellular plasticity, as it promotes epithelial cells to attain mesenchymal features. The protein TCF7L2 regulates the proliferation and differentiation of epithelial cells, however, whether TCF7L2 acts in an isoform-dependent manner to control EMT had remained largely to be elucidated. Transforming growth factor beta (TGFβ) signaling pathway is a potent inducer of EMT in normal and cancer conditions. How TGFβ-signaling-induced EMT is controlled is the subject of much investigations. The research carried out in this thesis tests the hypothesis that TCF7L2 acts in an isoform-specific manner to differentially regulate TGFβ-induced EMT in epithelial and carcinoma cells. Gain and loss of function studies were done to determine if alterations in the protein abundance of E, M, and S TCF7L2 isoforms affects EMT induction in cells grown in the context of a three-dimensional (3D) culturing system. Our data suggest that while TCF7L2E suppresses, TCF7L2M or S promotes TGFβ-induced EMT in 3D-multicellular structures derived from non-transformed epithelial cells or carcinoma cells. In other studies, we find that TGFβ signaling reduces the proportion of TCF7L2E to TCF7L2M/S protein in cells undergoing EMT. Mechanistically, we find that TCF7L2 operates via TGFβ-Smad signaling to regulate EMT. More recent studies have also identified a specific domain in the C-terminal end of TCF7LE isoforms to be required for its ability to suppress EMT. Collectively, our findings unveil novel isoform-specific functions for the transcription factor TCF7L2 and provide novel links between TCF7L2 and TGFβ signaling in the control of EMT and potentially cancer progression.
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Keywords
Epithelial-Mesenchymal-Transition (EMT), Breast cancer, TCF7L2 isoforms, TGFβ signaling
Citation
Karve, K. (2020). The Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.