Investigating the role of tumour derived hydrogen sulphide and its synthases in endometrial cancer tumourigenesis.



Avula, Laxshmi Veda
(2014) Investigating the role of tumour derived hydrogen sulphide and its synthases in endometrial cancer tumourigenesis. Master of Philosophy thesis, University of Liverpool.

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Abstract

Endometrial cancer is the 4th most common gynaecological malignancy in developed countries with a continual rise in incidence of >40% reported between the years of 1993-2007. Though endometrial cancer presents early with abnormal uterine bleeding the therapeutic options are limited with surgery being the hallmark treatment for these women. Recent evidence published has implicated the new gaseous transmitter hydrogen sulphide (H2S) in the pathogenesis of colorectal carcinoma. The results of this study strongly suggested a role for H2S synthase inhibitors as a possible therapeutic option. No prior studies have been conducted exploring the role of H2S in relation to endometrial carcinogenesis. This study aims to produce novel research exploring the role of H2S in endometrial carcinogenesis. Immunohistochemical techniques were used to stain a total of 81 human endometrial samples (post-menopausal n=16, complex atypical hyperplasias n=4 and endometrial cancers n=61) with H2S synthases i.e. Cystathionine-β-synthase (CBS), Cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MPST) to elucidate their differential expression between these groups. In vitro experiments were carried out investigating the effects of H2S donors i.e. GYY4137 and H2S substrates such as L-cysteine on the proliferative potential of the endometrial cancer cell known as MFE280. The results of this study concluded that the endometrium positively expresses all 3 enzymes. 3-MPST displayed higher levels of expression in the atrophic post-menopausal endometrium with a significant loss in its expression seen in low grade endometrial cancer cells (p<0.0001), suggesting a possible role for 3-MPST as an early disease marker. CSE like 3-MPST displayed a significant reduction in expression in cancerous cells when compared with post-menopausal and hyperplastic endometrium (p<0.001) whilst CBS showed no overall difference in expression between all study groups (p=0.136). Results of the in vitro investigations revealed an overall inhibition of cell viability of endometrial cancer cells when treated with a range of concentrations of H2S donors and substrates. Analysis of the above results presents a possible protective role of 3-MPST and CSE within the endometrium and their subsequent loss contributing to the development of endometrial carcinogenesis. Furthermore, the possibility of employing H2S donors as therapeutic agents in endometrial carcinomas may be a promising intervention and further functional studies will need to be conducted before conclusions regarding the latter can be determined.

Item Type: Thesis (Master of Philosophy)
Depositing User: Symplectic Admin
Date Deposited: 02 Jul 2015 01:53
Last Modified: 01 Feb 2017 15:29
URI: http://livrepository.liverpool.ac.uk/id/eprint/2002321
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