Ciz1 as a biomarker and drug target in Glioblastoma multiforme

Iwanowytsch, Olivia (2023) Ciz1 as a biomarker and drug target in Glioblastoma multiforme. Masters thesis, UNSPECIFIED.

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Glioblastoma (GBM) is the most prevalent primary brain tumour in adults with an extremely poor prognosis. The aggressive and infiltrative nature of these tumours renders them resistant to conventional therapies, posing a huge challenge in terms of treatment. As such, there is an unmet need for the development of more robust biomarkers to improve diagnostic and therapeutic strategies for high-grade gliomas. CIZ1 is a nuclear matrix associated-protein involved in various biological processes such as X chromosome localisation and inactivation, epigenetic maintenance and initiation of DNA replication. CIZ1 has been implicated in a number of common cancers including breast, prostate and lung. This work will focus on the role of CIZ1 in the initiation of DNA replication and the manipulation of CIZ1 in attempt to reduce growth and proliferation of primary GBM cell lines and unrelated tumour types in vitro. The role of CIZ1 as a diagnostic biomarker in GBM will also be assessed via immunohistochemistry (IHC) analysis using a cohort of patient-derived tissue sections. GBM cell lines require CIZ1 for efficient proliferation; chemical inhibition of CIZ1 with CDK and DDK inhibitors reduced CIZ1 protein levels and proliferative rates in U87-MG and BTNW914 cells. Whilst CIZ1 protein was not depleted, CIZ1 mRNA levels and cell proliferation reduced, S-phase progression also slowed. IHC analysis of FFPE patient- derived tissue sections revealed aberrant subcellular localisation of CIZ1. The mislocalisation of CIZ1 from the nucleus to the cytoplasm can differentiate between normal and tumour cells, implicating CIZ1 as a histopathological biomarker in GBM. Overexpression of CIZ1 was observed where the tumour intersection was visible, although further investigation using an expanded cohort of patient samples is required. Taken together these results support the use of CIZ1 as a biomarker and drug target in GBM; therapeutic approaches to reduce CIZ1 levels could be of clinical significance in the reduction of tumour growth.

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Thesis (Masters)
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14 Aug 2023 09:30
Last Modified:
21 Sep 2023 03:37