BACR 15: The identification and functional validation of microRNA-330-5p and microRNA-187 as regulators of sensitivity to chemoradiation therapy in oesophageal adenocarcinoma patients
1University of Hull, Hull, UK,2Trinity College, Dublin, Ireland
The standard of care for locally advanced OAC is neoadjuvant chemoradiation therapy (neo-CRT), prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of response to treatment has significant clinical implications in the therapeutic stratification for patients. Furthermore, understanding the molecular mechanisms underpinning tumour resistance to neo-CRT will identify novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNA function to regulate gene expression, and have been identified as modulators CRT response.
Pre-treatment OAC biopsy samples were analysed via qPCR based microRNA arrays. In vitro, the expression of select miRNAs was manipulated using overexpression and silencing plasmids. MiRNA targets were identified by whole transcriptome digital gene expression analysis. Xenografted OAC tumours were and established and mice were treated with cisplatin. Tumours were imaged with 18F-FDG PET.
MiR-330-5p and miR-187 were both downregulated in non-responders. In vitro miR-330 overexpression altered the E2F1/p-Akt signalling pathway, however the negative regulation of this pathway was not sufficient to alter cellular sensitivity to CRT. Silencing miR-330-5p did enhance cellular radioresistance. Furthermore, silencing miR-330-5p increased MMP1 protein expression and altered the expression of extracellular proteins. In vivo, our pilot data suggests initial growth was accelerated in tumours established from cells with miR-330-5p silencing and tumours were more resistant to treatment. In vitro, miR-187 overexpression induced apoptosis, and enhanced radiosensitivity.
In vitro miR-330-5p silencing enhanced, albeit subtly, cellular resistance to radiation. Considering work to identify gene targets has highlighted extracellular proteases, miR-330-5p may have additional functional roles in modulating the biology of the tumour microenvironment, which may facilitate altered tumour sensitivity and patient response to CRT. In vitro miR-187 enhanced cellular sensitivity to radiotherapy. MiR-330-5p and miR-187 may represent targets through which to augment tumour sensitivity to treatment and this is currently under investigation.