Functional analysis of prostate cancer-associated miRNAs using patient-derived xenografts
Project fact file
Drs Anna Grabowska, Vicky James, and Hari Ratan
School / Division
Schools of Medicine, Veterinary Medicine and Science
Technically-intensive/specialised research projects with high consumable costs
Prostate cancer represents an important cause of death and morbidity in contemporaryWestern society, being the second commonest cause of cancer death in men in the UK (1). Novel serum biomarkers for prostate cancer that can risk stratify patients more accurately than existing methods have the potential therefore to contribute greatly (2).
Plasma samples from localised prostate cancer patients, advanced prostate cancer patients and benign controls , were subjected to total RNA extraction, microRNA specific cDNA synthesis, and whole miRNome profiling of 754 unique miR sequences using microfluidic qRTLPCR arrays. Expression fold-change for each miR target across the three groups was calculated using the global mean expression level across the whole array as a control to identify probable targets that might discriminate between cancers and controls. Three miRs were found to be significantly downregulated in prostate cancer cases compared to benign controls and two miRs were upregulated.
We hypothesise that these miRNAs are involved in the regulation of key oncogenes or tumour suppressors that drive prostate cancer progression and, since they are found in the cell-free compartment in the circulation, we further hypothesise that they are associated with microvesicles or exosomes and involved in paracrine signalling within the primary tumours.
The aims of the project are to:
- to investigate the role of this set of miRNAs in prostate cancer via their over-expression or inhibition in tumour microenvironment (TME)-relevant pre-clinical prostate cancer models, followed by downstream phenotypic and molecular characterisation
- to investigate a potential role in paracrine signalling between cancer and stromal cells
1) Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12): 2893-917
2) Jackson B, Grabowska A, Ratan H (2014) MicroRNA in prostate cancer: functional importance and potential as circulating biomarkers. BMC Cancer 14(1): 930