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dc.contributor.advisorGuilford, Parry
dc.contributor.authorGaastra, Joel Bertus Ross
dc.date.available2015-11-15T20:36:49Z
dc.date.copyright2015
dc.identifier.citationGaastra, J. B. R. (2015). A search for synthetic lethality between Polo-like Kinase 3 and E- Cadherin (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/6075en
dc.identifier.urihttp://hdl.handle.net/10523/6075
dc.description.abstractHereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition caused by a mutation in the tumour suppressor gene E-cadherin, (CDH1). It predisposes to a 70% likelihood of developing highly penetrant diffuse gastric cancer. Because HDGC is driven by the absence of a tumour suppressor, conventional therapeutic approaches targeting tumour-promoting oncogenes cannot be used. Synthetic lethality is an approach that circumvents this issue by targeting vulnerabilities in cells that lack the functional tumour suppressor. This project aimed to investigate a potential synthetic lethal relationship between CDH1 and polo-like kinase 3 (PLK3), a cytoskeletal and cell cycle regulator. Lentiviral delivery of two shRNA were successful in knocking down PLK3 expression in isogenic MCF10A cell lines, with and without CDH1 expression (MCF10A and CDH1-/-). Viability was measured and confirmed as synthetic lethal (mutations in combination cause cells to be less viable) if the CDH1-/- cells were less viable with a ratio of ≤0.85. Results from one shRNA knockdown trended towards synthetic lethality (p > 0.05). Another shRNA resulted with a considerable reverse synthetic lethal effect, but was not statistically significant. PLK antagonists poloxipan and wortmannin were used to inhibit PLK3. Poloxipan induced reverse synthetic lethality with reduced viability in MCF10A cells at low concentrations. High concentrations produced a marginal synthetic lethal phenotype. Wortmannin’s effect on MCF10A and CDH1-/- cells also varied from synthetic lethal and reverse synthetic lethal. As the viability of CDH1 deficient cells could not be significantly reduced via PLK3 knockdown or inhibition, this candidate is no longer considered to be a potential therapeutic target for the treatment of HDGC.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectHDGC
dc.subjectCDH1
dc.subjectPLK3
dc.subjectSynthetic
dc.subjectLethality
dc.subjectPoloxipan
dc.subjectWortmannin
dc.subjectshRNA
dc.titleA search for synthetic lethality between Polo-like Kinase 3 and E- Cadherin
dc.typeThesis
dc.date.updated2015-11-15T20:09:51Z
dc.language.rfc3066en
thesis.degree.disciplineBiochemistry
thesis.degree.nameBachelor of Biomedical Sciences with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.openaccessOpen
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