| MOLECULAR
GENETIC CHANGES IN PROSTATE CANCER - GUIDES TO CLINICAL
MANAGEMENT.
Mark Feneley, Alex Freeman, Magali Williamson, Nicola Brookman-Amissah University College, London |
 |
The aim of the current project is to determine whether patients having radical prostatectomy with similar clinical and pathological features can be distinguished, based on specific molecular alterations in the prostate tumour, for predicting treatment failure.
The Prostate Cancer Research Centre, London, has been investigating various molecular factors that may determine progression of early stage prostate cancer following radical prostatectomy. This research has focused on a new technological angle - the role of a recently discovered class of RNAs, microRNAs (miRNAs), in prostate cancer progression.
miRNA’s are small pieces of nucleic acids that are believed to be involved in gene regulation. They may have potentially important effects on cancer behaviour, and provide new specific targets for novel treatments. The pattern of expression of various miRNAs in tissue represents its miRNA signature, and this appears to be altered in cancer. These signatures also may characterise cell types, lineages and cancer subtypes. To examine these signatures in surgical specimens of prostate cancer, intact RNA has to be extracted in sufficient quantity for analysis. Usually, mRNA extracted from tissue in paraffin blocks is very limited in quantity and frequently degraded. However, for analysis of the smaller miRNA molecules, we have successfully developed improved laboratory techniques for reliable analysis.
Our investigations have identified prostate-specific miRNAs that are altered in prostate cancer. Their expression in benign and malignant prostate cells has been compared demonstrating altered signatures. Abnormal miRNA patterns include increased expression of certain individual miRNAs and reduced expression of others. Cell migration and adhesion studies have then been carried out to relate altered miRNA expression to cell behaviour, comparing benign and malignant prostate cells. To further investigate the molecular function of miRNAs in cancer, individual miRNA expression in cell lines have been altered in our laboratory – some reduced by “knockdown” and others increased by “overexpression” - in preparation for further investigation of migratory and invasive capabilities. Having identified various miRNA signatures, and characterised associated changes in cell behaviour, further investigations will focus on the potential molecular targets.
The work completed so far suggests that miRNA expression is altered in prostate cancer. It supports the hypothesis that alterations in miRNA expression may influence cellular characteristics that underlie tumour behaviour. These preliminary findings open up a new field of research encompassing miRNAs in the prostate and their application in clinical therapeutics.
Summary of final research report by Mr Feneley, dated 15 August
2008
Project 2005/17