Abstract
Prostate carcinoma contain foci of neuroendocrine transdifferentiation, resulting in an increase of androgen-independent neuroendocrine-like (NE) tumor cells, whose number significantly correlates with tumor aggressiveness and thus lower survival rate. Neuroendocrine transdifferentiation of prostate cancer cells and a potential role of miRNAs within this process are poorly understood. MicroRNAs are small non-coding RNAs which post-transcriptionally regulate gene expression. The aim of this project was to identify new genes and miRNAs involved in neuroendocrine transdifferentiation. LNCaP prostate cancer cells were differentiated to NE-like cancer cells and microarray analyses were performed. Microarray results have been validated for the eight most deregulated mRNAs and microRNAs via qRT-PCR and analyzed with different algorithms to predict new targets for deregulated microRNAs. The induced CyclinD1 gene could be validated as new target gene for the repressed miR-17 family containing miR-17, miR-20a, miR-20b, miR-106a and miR-106b via reporter gene assays and Western Blot. Functional analysis of miR-17 family shows a high influence on cell proliferation, colony forming ability and apoptosis in LNCaP cells. Our data demonstrate wide changes in mRNA and microRNA expression during neuroendocrine transdifferentiation of LNCaP cells and confirm new mRNA-miRNA interactions with potential roles in NE-transdifferentiation of prostate carcinoma.
Highlights
Prostate cancer (PCa) is the second most common diagnosed cancer type in male worldwide contributing 15% of the total number of new cancer cases diagnosed
We show an impact of miR-17, -20a/b and -106a/b on the expression of their target gene CCND1 as well as on growth behavior and apoptosis of LNCaP cells to confirm the impact of miRNA deregulation during neuroendocrine transdifferentiation (NETD) of prostate cancer cells
To confirm NETD we examined marker gene expression in a time course experiment including androgen receptor (AR), neuron-specific enolase (NSE), prostate-specific antigen (PSA), neurotensin (NTS) and tubulin beta III (TUBB3)
Summary
Prostate cancer (PCa) is the second most common diagnosed cancer type in male worldwide contributing 15% of the total number of new cancer cases diagnosed. Two thirds of cases of prostate cancer are diagnosed in the western world and lead to a major health problem in many industrialized countries [1]. Androgens are one critical factor for the development and progression of prostate tumors and are the main therapeutic target consisting of androgen depletion or androgen receptor (AR) blocking in advanced and metastatic prostate cancer disease. Most patients relapse and develop androgen-independent and more aggressive forms of prostate cancer without promising cure options [2].
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