One in six men will be diagnosed with prostate cancer in the United States but only a subset of these individuals will progress to more advanced and lethal forms of the disease. Currently, there are no biomarkers available to distinguish aggressive from indolent prostate cancer and therapeutic options for castration resistant and metastatic disease are inadequate. MicroRNAs (miRNAs) belong to a growing class of small noncoding RNAs that hold promise as effective biomarkers and therapeutic targets for prostate cancer. These ~22 nucleotide noncoding RNAs are involved in posttranscriptional regulation of a wide range of biological processes related to cell proliferation, differentiation, and apoptosis. miRNAs act as negative regulators of gene expression by binding to complementary sequences within their target messenger RNAs (mRNAs) resulting in a block in protein translation and/or mRNA degradation of the target. Aberrant miRNA expression is often observed in prostate cancer patients. Accumulating evidence indicates that individual miRNAs act as tumor suppressor genes or oncogenes in the prostate to regulate cancer progression pathways associated with proliferation, migration, invasion, epithelial to mesenchymal transitions, metastasis, and androgen response. The recent detection of circulating miRNAs and exosomal miRNAs in body fluids such as plasma, serum, and urine reveal great potential for small RNAs in the clinic as noninvasive diagnostic and prognostic biomarkers for prostate cancer. Increased understanding of the molecular mechanisms involved for miRNAs during cancer progression will allow the translation of this exciting research into the clinic. This chapter summarizes the role miRNAs play in regulating prostate cancer progression and metastasis and discusses their potential as effective biomarkers and cancer therapeutic targets for this prevalent and deadly disease.

MicroRNAs (miRNAs) are important regulators of cell fate determination and homeostasis. Expression of these small RNA genes is tightly regulated during development and in normal tissues, but they are often misregulated in cancer. MiRNA expression is also affected by DNA damaging agents, such as radiation. In particular, mammalian miR-34 is upregulated by p53 in response to radiation, but little is known about the role of this miRNA in vivo. Here we show that Caenorhabditis elegans with loss-of-function mutations in the mir-34 gene have an abnormal cellular survival response to radiation; these animals are highly radiosensitive in the soma and radioresistant in the germline. These findings show a role for mir-34 in both apoptotic and non-apoptotic cell death in vivo, much like that of cep-1, the C. elegans p53 homolog. These results have been additionally validated in vitro in breast cancer cells, wherein exogenous addition of miR-34 alters cell survival post-radiation. These observations confirm that mir-34 is required for a normal cellular response to DNA damage in vivo resulting in altered cellular survival post-irradiation, and point to a potential therapeutic use for anti-miR-34 as a radiosensitizing agent in p53-mutant breast cancer.

In C. elegans, heterochronic genes control the timing of cell fate determination during development. Two heterochronic genes, let-7 and lin-4, encode microRNAs (miRNAs) that down-regulate a third heterochronic gene lin-41 by binding to complementary sites in its 3'UTR. let-7 and lin-4 are conserved in mammals. Here we report the cloning and sequencing of mammalian lin-41 orthologs. We find that mouse and human lin-41 genes contain predicted conserved complementary sites for let-7 and the lin-4 ortholog, mir-125, in their 3'UTRs. Mouse lin-41 (Mlin-41) is temporally expressed in developing mouse embryos, most dramatically in the limb buds. Mlin-41 is down-regulated during mid-embryogenesis at the time when mouse let-7c and mir-125 RNA levels are up-regulated. Our results suggest that mammalian lin-41 is temporally regulated by miRNAs in order to direct key developmental events such as limb formation.

MicroRNAs (miRNAs) are regulatory molecules that negatively control gene expression by binding to complementary sequences on target mRNAs. The most thoroughly characterized miRNAs, lin-4 and let-7, direct cell fate determination during the larval transitions in C. elegans and act as key regulators of temporal gene expression. lin-4 and let-7 are founding members of two distinct families of miRNA genes sharing strong sequence homology primarily in the 5' end of the mature miRNAs. In this report, we characterize the temporal and spatial expression patterns of lin-4 and let-7 family members using northern blot analysis and mir::gfp fusion studies. Our results show that lin-4 and let-7 homologues possess distinct temporal and spatial expression patterns during nematode development and that known heterochronic genes regulate their expression. We find that certain lin-4 and let-7 family members display overlapping expression patterns in the hypodermis and the reproductive system, suggesting that combinations of miRNAs from across families may control common developmental events.