Oesophageal cancer is the eight most common cancer and the sixth leading cause of deaths worldwide. There are two major histological subtypes of oesophageal cancer, with the most predominant subtype in Europe and the USA being oesophageal adenocarcinoma (OAC). The standard of care for OAC patients with locally advanced disease is neoadjuvant therapy and surgical resection. Unfortunately, ~70% of patients do not respond to neoadjuvant therapy and non-responders gain no benefit from the aggressive treatment regimen whilst compromising their quality of life. There is an unmet clinical need for biomarkers predicative of patient's response to neoadjuvant chemoradiation therapy (neo-CRT). In a pre-treatment setting, predictive biomarkers indicative of patient response could enable the stratification of patients and would ensure individual patients receive the most effective treatment. However, the greater clinical benefit for patients may come from the development of new or combination therapeutics for OAC. Novel chemosensitising and radiosensitising therapeutics could be administered with neo-CRT to enhance tumour sensitivity, improve CRT efficacy and increase survival rates for OAC patients. MicroRNAs (miRNA/miRs) are short non-coding RNA that function to regulate gene expression at the post-transcriptional level. A single miRNA can potentially target hundreds or thousands of mRNA and subsequently alter the expression of multiple genes and proteins. As essential regulators of gene expression, miRNA are involved in all cellular processes and are dysregulated in cancer and other diseases. Furthermore, miRNA have been identified as predictors and modifiers of tumour sensitivity to chemotherapy and radiotherapy in numerous cancer types. Playing a causal role in disease development and progression, miRNA are promising biomarkers and therapeutic targets. In this study miRNA were investigated as biomarkers of OAC patient response to neo-CRT and as potential therapeutic targets through which to enhance tumour sensitivity to neo-CRT. In pre-treatment OAC biopsies, 67 miRNA that were differentially expressed between responders and non-responders to neo-CRT were identified. MiR-330-5p and miR-187 were downregulated in the pre-treatment biopsy samples of the neo-CRT non-responders. The functional roles of miR-330-5p and miR-187 were investigated as modulators of tumour sensitivity to CRT. In vitro the silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to radiation. Furthermore, silencing miR-330-5p altered the expression of extracellular proteases and protease inhibitors, including MMP1. In vivo a pilot study indicated miR-330-5p silencing enhanced tumour growth and may alter tumour sensitivity to cisplatin. In vitro miR-187 overexpression enhanced cellular sensitivity to radiotherapy and cisplatin, implying that the downregulated miR-187 expression in the non-responders may confer resistance to CRT. Furthermore, miR-187 induced apoptosis in vitro and induction of apoptosis is a potential mechanism by which miR-187 enhances radiosensitivity. MiR-187 altered the expression of genes encoding extracellular proteins, including C3 and other immune related genes. Both miR-330-5p and miR-187 are potential regulators of the secretome, thus emphasising the role of miRNA as modulators of the tumour microenvironment. This study has identified miR-330-5p and miR-187 as potential therapeutic targets that could augment OAC tumour sensitivity to neo-CRT.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:769086 |
| Date | January 2015 |
| Creators | Bibby, Becky Ann Selina |
| Contributors | Maher, Stephen G. |
| Publisher | University of Hull |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hydra.hull.ac.uk/resources/hull:17129 |
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