The roles of microRNAs in the anti-cancer effects of sulforaphane from cruciferous vegetables

Dacosta, Christopher (2017) The roles of microRNAs in the anti-cancer effects of sulforaphane from cruciferous vegetables. Doctoral thesis, University of East Anglia.

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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.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Jackie Webb
Date Deposited: 28 Jun 2017 13:43
Last Modified: 31 Mar 2018 00:38


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