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Title: WWOX, tumour suppressor and modifier gene, as a regulator of gene expression and apoptosis in ovarian cancer
Author: Janczar, Szymon Lech
ISNI:       0000 0004 2688 6786
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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WWOX is a tumour suppressor gene, as demonstrated by increased neoplasia incidence in Wwox-knock-out animals, and is frequently disrupted in human cancers. WWOX expression reconstitution abolishes xenograft growth of lung, pancreatic, breast, ovarian and prostate cancer cells. The tumoursuppressive function of WWOX is suggested to be related to pro-apoptotic effects or interactions with potentially oncogenic transcription factors leading to their cytoplasmic sequestration and trans-activity inhibition. In physiology WWOX might be involved in metabolism. Our group demonstrated that WWOX reconstitution in ovarian cancer cells inhibits xenograft growth but this was not accompanied by altered in vitro growth or apoptosis rates. Rather, WWOX transfection reduced cancer cell adhesion to extracellular matrix due to reduction of integrin α3 binding. Additionally, our group postulated that natural polymorphic variants of WWOX are linked to ovarian cancer clinicopathological features. The hypotheses behind this work were that WWOX regulates gene expression or promotes apoptosis in ovarian cancer. Further, this project aimed at confirming the associations of WWOX polymorphisms. I demonstrate no link between WWOX status and the subcellular localization of putative WWOX-binding transcription factors or the expression of their target genes in ovarian cancer cells. The phenotypic consequences of WWOX expression manipulation do not appear to be explained by transcriptional changes. I show that WWOX increases apoptosis rates in ovarian cancer cells exposed to the chemotherapy agent paclitaxel, but not cisplatin. This is independent of the anti-mitotic function of taxanes and unrelated to integrin regulation. Rather, WWOX promotes cell death during taxane-induced endoplasmic reticulum stress. I propose WWOX-driven cell death during endoplasmic reticulum stress might be also linked to anti-tumorigenic effects in vivo. A validation study did not confirm the link between WWOX genetic variants and ovarian cancer pathology. There is also no link between WWOX polymorphisms and bone metabolism, a trait affected in WWOX-knock-out animals.
Supervisor: Gabra, Hani Sponsor: Ovarian Cancer Action
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral