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Title: The roles of microRNAs in the anti-cancer effects of sulforaphane from cruciferous vegetables
Author: Dacosta, Christopher
ISNI:       0000 0004 6351 1772
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2017
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Colorectal cancer is an increasingly important cause of mortality, whose incidence is inversely correlated with cruciferous vegetable consumption, from which can be obtained isothiocyanates such as sulforaphane. These are well-characterised regarding their cytoprotective and anti-tumour effects, thus believed to contribute to the observed diet-risk correlation; great interest lies in their potential use for chemoprevention and/or improvement of chemotherapy. While some mechanisms of action are well-established, such as their induction of antioxidant responses via the Nrf2 pathway, questions remain regarding its other mechanisms of action that appear to be vast and complex, more knowledge of which could shine a light upon means of safe and effective clinical application. There is evidence that sulforaphane can modulate the expression of microRNAs, which play major roles in development and disease by regulating gene expression, particularly in carcinogenesis. This study explored sulforaphane-induced microRNA modulation in adenocarcinoma Caco-2 and non-cancerous CCD-841 colorectal cells, and the potential role of such in the interactions between sulforaphane and colorectal carcinogenesis. The experimental system was initially validated by confirming the expected induction of Nrf2 and Nrf2- controlled genes at the mRNA and/or protein levels, by sub-cytotoxic doses of sulforaphane. Based upon data from the following miRNA-Seq-based expression profiling and individual microRNA assays, sulforaphane upregulated let-7f-5p and let-7g-5p expression in Caco-2 but not in CCD-841 cells, and upregulated miR-10a-5p and downregulated miR-193b-3p in Caco- 2. The direct interaction of let-7f-5p with computationally-predicted mRNA-3’- UTR binding sites of cell division cycle 25 homolog A and high-mobility group AT-hook 2 was confirmed by luciferase assays. Future experiments to confirm the effects of sulforaphane and/or let-7f-5p on these genes at the protein/mRNA levels could be informative, as could tests for synergistic and/or antagonistic interactions between sulforaphane and let-7f-5p. Insights from such experiments could eventually lead towards the development of more effective chemopreventative and chemotherapeutic strategies based upon sulforaphane and/or specific microRNA mimics/inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available