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Rusu, Alexandra Doina (2020) Novel roles for CG7379/ING1 in tumour progression: a study of migration and invasion using in vivo and in vitro epithelial systems. PhD thesis, University of Nottingham.

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Abstract

The ability of cancer cells to invade and metastasize is the hallmark of cancer that sets apart malignant from benign tumours. Approximately 90% of cancer-related deaths can be attributed to cancer’s ability to spread. A recent in vivo genetic screen that focused on the identification of tumour progression modulators identified CG7379, the fly orthologue of human ING1, as a potential invasion suppressor. ING1 is a type II tumour suppressor gene with well-established roles in transcriptional regulation of genes that control cell proliferation, response to DNA damage, oncogene-induced senescence and apoptosis. Recent work suggests a possible role for ING1 in cancer cell invasion and metastasis; however the underlying molecular mechanism has not been studied thus far.

In the present work, we took a loss-of-function approach to uncover the molecular mechanism employed by CG7379/ING1 to modulate single cell invasion in vivo and in-vitro respectively. Our results show that: i) reduced expression of CG7379 induces invasion and brain metastasis in vivo in Drosophila and further cooperates with a loss of polarity mutation to intensify the invasive phenotype. Similarly, ING1 knockdown significantly enhances invasion in vitro in a human breast cancer model; ii) CG7379 knockdown reduces the junctional localisation of several adherens and septate junction components and severely disrupts cell-cell junction architecture. Similarly, decreased expression of ING1 disrupted E-cadherin distribution at cell-cell junctions in vitro, presumably by regulating cytoskeletal dynamics at the transcriptional level; iii) Both CG7379 and ING1 knockdown negatively impact cell proliferation, leading to decreased tumour size and cell accumulation in G0/G1 at 48 hr post-transfection respectively.

Taken together, the results presented in this thesis highlight the complexity of ING1 mediated transcription regulation and suggest that the multiple tumour suppressor effects associated with CG7379 and ING1 are likely to be coordinated at the transcriptome level.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Georgiou, Marios Rahman, Ruman
Keywords:	CG7379, ING1, invasion, cancer, Antioncogenes
Subjects:	R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	61777
Depositing User:	Rusu, Alexandra
Date Deposited:	02 Oct 2023 07:44
Last Modified:	02 Oct 2023 07:44
URI:	https://eprints.nottingham.ac.uk/id/eprint/61777

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