The emerging roles of BAP1 and cancer stem cells in Malignant Mesothelioma

Guazzelli, A 2019, The emerging roles of BAP1 and cancer stem cells in Malignant Mesothelioma , PhD thesis, University of Salford.

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Abstract

Malignant Mesothelioma (MMe) is an aggressive asbestos-related cancer with a poor prognosis and the standard treatments are not effective. The lack of successful therapies is due to several factors, including the poor knowledge of mesothelioma biology. In this thesis, several biological aspects have been investigated. Recent studies have found that a percentage of MMe patients is carrying germline or somatic mutations in (BRCA1-associated protein 1) BAP1 gene. BAP1 is a deubiquitinase and a tumour suppressor, involved in cell cycle, apoptosis, epigenetic modifications and DNA damage response. Herein, it has been demonstrated that BAP1 mutated and silenced MMe cells are more resistant to a DNA damage drug, gemcitabine, causing the reduction of the DNA damage effect of gemcitabine. These finding suggested that BAP1 modulates chemosensitivity though DNA damage response and provided a potential route for more efficient MMe therapy. A recent study demonstrated that BAP1 regulates the inositol 1,4,5-trisphospate receptor subtype 3 (IP3R3)-mediated calcium flux. Cancer Stem-like Cells (CSCs) are a small population within the tumour mass, which are responsible for tumour initiation, cancer progression and treatment failure. Increased evidence suggests that CSCs rely on mitochondria function as the main source of energy. Therefore, this thesis assessed the role of BAP1 in the modulation of stem cell-like features through IP3R3-mediated calcium flux from endoplasmic reticulum (ER) into mitochondria in BAP1 wild type, mutated and silenced MMe cells. BAP1 and IP3R3 silencing caused reduction in the number of CSCs as measured by mesospheres formation, however markers of stemness such as Aldehyde dehydrogenases (ALDH) did not confirm stemness features and further investigations are required. In conclusion, in this thesis novel molecular circuits in mesothelioma were identified, providing further insight into understanding complex biology of this cancer and suggesting potential approach for improving clinical outcomes.

Item Type: Thesis (PhD)
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Funders: GIMe
Depositing User: Alice Guazzelli
Date Deposited: 09 Oct 2019 12:38
Last Modified: 16 Oct 2019 09:37
URI: http://usir.salford.ac.uk/id/eprint/52444

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