Gene expression regulation by miR-221: A novel mechanism in prostate cancer progression

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Prostate cancer (PCa) is the most common non-skin malignancy in the male population. In Europe approximately 90.000 men die of the disease every year and despite several initiatives to reduce mortality this number has still not dropped significantly. This is primarily due to the fact that when the tumor has spread locally, no curative intervention is available, and the patient will ultimately develop metastatic disease that is unresponsive to currently available androgen deprivation therapy and chemotherapy. Micro-RNAs, small non-coding RNA molecules play pivotal roles in carcinogenesis and can function either as tumor suppressor or oncogenic-miRs. Micro-RNA expression studies have shown that there are characteristic miRNA signatures in PCa and extensive evidence has indicated that miR-221 is one of the most frequently and strongly downregulated miRNAs in primary PCa. MiR-221 is downregulated in aggressive PCa, lymph node metastasis and is an independent predictor for PCa related death. MiR-221 regulates cell growth, invasiveness and apoptosis at least partially via STAT1/STAT3 mediated activation of the JAK/STAT signaling pathway by directly inhibiting the expression of SOCS3 and IRF2, two oncogenes known to be negative regulators of the JAK/STAT signaling pathway and sensitizes PCa cells for interferon- gamma mediated growth inhibition in vitro. Thus we hypothesize that miR-221 may contribute to control of prostate cancer progression and metastasis by regulating cytokine signaling and aim to elucidate miR-221 functional effects triggering progression and metastasis in PCa.