The role of Ca2+ signalling and bile acids in the biology of Barrett's oesophagus and oesophageal adenocarcinoma
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Date
2024
Authors
Cutliffe, Alana
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Publisher
University College Cork
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Abstract
Oesophageal adenocarcinoma (OAC) is highly prevalent in Ireland (1.8 per 100,000 persons), is on the rise and is associated with poor patient survival (5-year survival of less than 15%). There is a high rate of recurrence (up to 50% after an oesophagectomy) and the neoadjuvant chemotherapy response rate is 32%. A precursor condition, Barrett’s oesophagus (BO), is associated with hydrochloric acid and bile acid (BA) reflux from the stomach. Little is known about how oesophageal cells interact with acidic and BA environments and remodel to form BO or OAC. Such effects may be mediated via Ca2+ signalling, but little work on the topic has been carried out to date. The aim of this study was to investigate the role of Ca2+ signalling (Research Objective A) and BA exposure (Research Objective B) in the development or prevention of BO and OAC. A transcriptomic analysis of 275 Ca2+ signalling genes was carried out on two independent OAC datasets (Research Objective A) and a systematic review (¬20 studies) was carried out on neutral-pH, BA exposure in the prevention and development of BO and OAC (Research Objective B). Of the 275 Ca2+-toolkit genes analysed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Six highly expressed genes were associated with improved patient survival: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). The six genes in question were also upregulated in advanced OAC tumor grades and nodal, metastatic stages. Key observations in the BA systematic review were that deoxycholic acid exerted effects on induction of BO and OAC through several potentially co-operating mechanisms, including oxidative stress, DNA damage, inflammation, proliferation, apoptosis, apoptotic resistance and angiogenesis. In BO, taurodeoxycholic acid was associated with oxidative-stress and DNA damage. Treatment of non-malignant human oesophageal cells and BO cells with ursodeoxycholic acid in vitro resulted in a reduction of deoxycholic-acid-induced inflammation. In conclusion, both Ca2+ signalling and BA exposure may play a role in the development of BO and OAC. Ca2+ signalling is relatively understudied in cancer and may provide novel therapeutic avenues and a reduction in side-effects. BAs could be targeted therapeutically, through medication, bacterial supplementation, or lifestyle modifications. The possibility of a reduced side-effect therapy and lifestyle interventions are of great appeal to cancer patients. The results presented in the current study lay the groundwork for highly informed laboratory research hypotheses.
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Keywords
Oesophageal adenocarcinoma , Barrett's oesophagus , Ca2+ signalling , Bile acids , Gastro-oesophageal reflux disease
Citation
Cutliffe, A. 2024. The role of Ca2+ signalling and bile acids in the biology of Barrett's oesophagus and oesophageal adenocarcinoma. MRes Thesis, University College Cork.