The Role of MicroRNAs in Prostate Cancer Progression

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DESCRIPTION (provided by applicant): Prostate cancer is the most common form of cancer in males within the United States. This prevalent disease was responsible for ~27,000 deaths last year, a mortality rate in men second only to lung cancer. Prostate-specific antigen (PSA) is a widely used diagnostic marker for prostate cancer that can result in the treatment of insignificant disease due in part because PSA is tissue specific but not prostate cancer specific. Therefore, more accurate biomarkers, potentially used in combination with PSA, are required to aid in the early diagnosis of prostate cancer. An abundant class of small non-coding RNAs of ~22 nucleotides in length, referred to as microRNAs (miRNAs), are often misexpressed in human cancers and implicated to function as tumor suppressors and oncogenes. However, little is known regarding how these molecules directly contribute to cellular transformation and cancer progression or how miRNA deregulation relates to prostate cancer. SPECIFIC AIMS: The hypothesis to be tested is that miRNAs controlling proper cellular growth and differentiation in the prostate will be deregulated in the diseased state and thus miRNA misexpression will closely correlate with early stages of prostate cancer progression and micrometastatic disease. We particularly anticipate identifying members of the evolutionary conserved lin-4 and let-7 miRNA families, which we have shown control essential developmental events in animals and are linked with human cancers. This proposal will 1) identify miRNAs that are deregulated in a large cohort (~250) of tissue samples taken from patients with prostate carcinomas including insignificant and micrometastatic disease compared to non-cancerous specimens from benign prostatic hyperplasia (BPH) patients and normal prostate tissues via miRNA microarray analysis and quantitative real-time PCR; 2) determine the gene targets of prostate cancer-associated miRNAs that direct oncogenic events using bioinformatic screens and reporter gene assays; and 3) investigate if these prostate cancer-associated miRNA-target interactions are directly involved in cancer progression by in situ expression analysis on normal and diseased prostate tissue specimens and miRNA misexpression studies in human prostate cell lines to analyze resulting affects on growth modulation and cellular transformation. The overall goal of this proposal is to identify miRNA genes that could serve as early detection biomarkers for prostate cancer and to determine how these miRNAs and their potential targets control tumor formation in this tissue. Investigating the function of miRNAs in prostate cancer progression promises to reveal novel strategies to detect & treat this prevalent disease.