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Title: The evaluation of the effects of the Mitotic Arrest Deficiency Protein 2 (MAD2) and the miR-433 microRNA on chemoresistance and cancer prognosis
Author: Byrne , Tara
ISNI:       0000 0004 6423 886X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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Chemoresistance is a major obstacle in the treatment of high-grade serous ovarian cancer (HGSOC) hence identification of molecular markers of chemoresistance is of crucial importance. The primary focus of this thesis is to investigate the prognostic potential of the miR-433 microRNA target, mitotic arrest deficiency 2 protein (MAD2). In order to do this, MAD2 expression was evaluated in three HGSOC cohorts and was found not to correlate with survival. An association between MAD2 expression in neoadjuvant treated HGSOC patients and survival was evident. MAD2 levels therefore may be of prognostic value in this subgroup of patients. We previously described miR-433 as a critical cell cycle regulator and mediator of cellular senescence. In an attempt to determine whether miR-433 infers a survival advantage under chemotherapeutic selective pressures, a miR-433 overexpressing cell line was developed. Here, we have shown that higher miR-433 expression was associated with an increased resistance to platinum, which was unrelated to loss of MAD2 expression. Moreover, cells which remained viable following exposure to high doses of chemotherapy expressed higher levels of miR-433. Our data suggests that chemotherapy may not be driving the transcriptional up-regulation of miR-433 but rather selecting a population of cells with high miR-433 expression that escape chemotherapeutic kill. IHC analysis by our group of the miR-433 target, histone deacetylase 6 (HDAC6), previously, confirmed that its expression was significantly associated with a decrease in overall survival in HGSOC patients. In this thesis, the inhibition of HDAC6 in HGSOC cells did not attenuate apoptotic responses to paclitaxel. Therefore we suggest that HDAC6 inhibitors should not be recommended in conjuction with paclitaxel for HGSOC treatment. In conclusion, miR-433 and its target proteins play an important role in chemoresistance in HGSOC and could be measured or manipulated for potential therapeutic benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available