Translational and functional analyses of microRNAs in prostate cancer

Abstract: The aims of this thesis were to identify microRNAs (miRNAs) with prostate cancer prognostic and diagnostic potential, to discover miRNAs with therapeutic capacity against prostate cancer, and to investigate if prostate specific antigen (PSA) is miRNA regulated. Prostate cancer is a globally spread disease with low mortality, but some patients develop an aggressive lethal form of prostate cancer with severe morbidity. In the early nineties the PSA test was introduced as a blood based test that has high sensitivity for prostate cancer. The possibility to set prognosis by this test is however limited. For men that may develop incurable aggressive prostate cancer, there is therefore an urgent need for novel biomarkers and therapeutics, so that these are detected and more correctly treated at an early stage. miRNAs are molecules that have post-transcriptional regulatory capacity, by binding their target transcripts. The miRNA profile has been shown to be deregulated in cancer cells, which can lead to elevated or inhibited expression of their targets. The effect can be increased or decreased expression of oncogenes or tumour suppressors respectively. By analysing prostatic tissues from men with and without prostate cancer, we found that the levels of four miRNAs (miR-96, -145, -183, and -221), in an algorithm denoted miQ, can in addition to set the correct diagnosis, predominantly of PSA, predict metastases and tumour aggressiveness. Further, patients with high miQ levels lived three years longer after surgery compared to patients with low miQ. The miQ profile is highly translational to the clinic. The biological function of miR-145 was investigated and found to inhibit androgen induced cell growth and to regulate the androgen receptor; therefore it is a good therapeutic candidate. Exploring functionality of miR-96 in prostate cancer, we found that it has good potential to be targeted therapeutically. The antiproliferative protein FOXO1 was found to be a direct target of miR-96, explaining the cell growth promoting effect of miR-96. By an extensive screening for miRNAs that affect PSA levels, we found that miR-183 increases its expression. This implies that miR-183 has an effect on the PSA test, today used for detection of prostate cancer. All three functionally studied miRNAs have individually diagnostic and prognostic properties, but combined into miQ the individual qualities enhances each other. To conclude, we found a miRNA profile that is associated with both prostate cancer prognosis and diagnosis, miRNAs have therapeutic potential, and can influence the PSA detection method.