Predictive Capacity and Functional Significance of MicroRNA in Human Melanoma

Melanoma is one of the most serious forms of cutaneous malignancies with an incidence of over two million people worldwide1. During 2010, an estimated 68,130 new patients were diagnosed with melanoma, and 8,700 deaths were attributed to the development of metastatic disease in the United States2. Compared to earlier stages of melanoma, the prognosis for patients with metastatic (stage IV) melanoma is very poor with six out of every seven skin cancer-related deaths being attributed to melanoma. However, our diagnostic and prognostic methods for melanoma are primarily histologic, such as Breslow’s depth of invasion, falling far short of being able to accurately predict the overall survival, recurrence risk, or clinical outcomes for patients3. There are several methods of treatment for metastatic melanoma, including radiation therapy, immunotherapy, chemotherapy, and palliative surgery2, 4, 5. However, there exists a clear and unfortunate understanding that these therapies are only minimally effective in treating patients with advanced disease6. MicroRNAs(miRNAs) are a set of small, average 22 nt in length, single-stranded, non-proteincoding RNA molecules that can recognize and bind 3’-untranslated regions (UTR) of mRNA, blocking translation of the gene or inducing cleavage of the mRNA7, 8. To date, a total of 15,172 miRNAs (Version 16.0), including 1,049 human miRNAs, have been registered in the miRbase database. The biogenesis of miRNA is similar to the other RNA starting from DNA transcription. A primary miRNA (pri-miRNA) is an independent transcript processed by RNA polymerase II (Pol II), which are bound in the nucleus by the microprocessor complex consisting of the RNase III-type endonuclease, Drosha, and its co-factor, Pasha (DGCR8). These enzymes can crop the pri-miRNA into a hairpin loop, cleaving off 3’ and 5’ regions of excess mRNA to give precursor miRNA (pre-miRNA) ~70 nt in length. Pre-miRNA is then actively transported to the cytoplasm by exportin-5 where it is bound by the RNAse III-type endonuclease, Dicer, which removes the loop, resulting in a duplex of complementary, mature miRNA sequences. One strand is bound by the RNA-induced silencing (RISC) complex, which guides mature miRNA to target mRNA for subsequent silencing. The remaining strand is usually degraded, but it may be bound by RISC and target its own mRNAs, which are denoted with an asterisk (i.e., miR-10b and miR-10b*)9, 10. In both plants and animals, miRNAs are capable of mediating gene expression by influencing the RNA’s stability and/or translational resspression11, 12. Impressively, a single