microRNA and regulation of MED in prostate cancer

Prostate cancer is the second most common malignant tumor in men with more than 1 million new cases diagnosed annually. Curative treatment by surgery and radiotherapy is possible in early tumor stages. Androgenic hormones bind to the receptor and regulate proliferation and apoptosis in prostate cancer. Administration of novel anti-androgens led to improvement in patients survival. However, novel research approaches frequently consider newly described oncogenes. Regulatory mechanisms responsible for prostate cancer progression are of substantial interest in clinical medicine. Recently, the role of mediator (MED) complex in prostate cancer development and progression has been established. The subunits MED12 and MED15 are highly expressed in patients tissues, in particular in castration therapy-resistant prostate cancer. The main aim of our project is to investigate the mechanisms of MED12 and MED15 upregulation and possible effects of tumor-adjacent stromal cells on elements of the MED complex. In this context, we will focus on small non-coding microRNAs (miRNAs) which are known to act either as oncogenes or tumor suppressors and are deregulated in prostate cancer. In order to analyze the role of miRNA in regulation of MED complex, we will examine whether they affect sensitivity of castration therapy-resistant prostate cancer to the anti-androgen enzalutamide and inhibitor of androgen synthesis abiraterone. The therapeutic application of miRNAs will be studied also in vivo in order to test the possibilites for improvement of therapy for prostate cancer. We also plan to examine the expression of MED12/MED15 and their regulating miRNAs in specimens obtained from patients with advanced prostate cancer. In order to better understand the role of the tumor microenvironment in miRNA/MED complex interactions, we will use stromal cell cultures representing different cancer phenotypes. Finally, we will examine the possibility that combined miRNA replacement will lead to resensitization of cells to androgenic stimulation. Taken together, our experimental approaches may help to identify novel tumor suppressive miRNA and improve prostate cancer therapy.

Prostate cancer is a disease which affects elderly man. It could be completely cured in earlier stages by radical prostatectomy. Prostate cancer in more advanced stage could be partially inhibited by androgen receptor antagonists. After a certain period of time, the disease progresses and other types of therapy such as chemotherapy should be tried. Androgen receptor is expressed at later stages in prostate carcinogenesis and its inhibition is high priority in prostate cancer research and treatment. For this reason, it is important to learn more about the regulators of androgen receptor activity and cellular proliferation in prostate cancer. We focused on MED12 in different cellular models representing prostate cancer. Androgen receptor-positive cell lines were more sensitive after inhibition of expression of MED12. We also investigated a possible relationship between MED12 and c-Myc because c-Myc is an oncogene involved in many cellular functions. Interestingly, inhibition of MED12 caused also inhibition of c-Myc thus also contributing to potential anti-tumor effect. We then focused on MED12 and variants of androgen receptor which are constitutively active. These variants are increasingly expressed in prostate cancer resistant to endocrine therapy. Similar to previous findings, we also obtained evidence that inhibition of MED12 causes down-regulation of full-length and constitutively active androgen receptors. Taken together, our findings open a new possibility to inhibit androgen receptor and cellular proliferation in advanced prostate cancer.