Microrna Oncogenes And Tumor Suppressors Controlling Malignant Melanoma Cell Growth, Apoptosis, Migration, And Invasion.

8549 Background: Melanoma incidence is increasing faster (3%-7% per annum) than any other cancer. Data from the SEER Study showed a melanoma incidence rate of 19.5/100,000 for males and 14.4/100,000 for females in the USA, resulting in roughly 14,000 cases/year in the USA alone. Emalignant melanomas are generally easily treated by resection; but treatment ability changes dramatically once the tumor becomes metastatic. Such patients have a five year survival rate less than 5%, with median survival of only six to twelve. Dacarbazine (DTIC) is the only approved treatment for malignant melanoma, yet patient responses are infrequent (~10-20% of patients). Even in responders, DTIC extends lifespan for only 3-6 months. Methods: We examined the function, of miRs found to be differentially expressed in thirty-six melanoma skin biopsies compared to sixteen normal donor skin biopsies, on cell growth rate, caspase 3/7 activation, migration, invasion, and susceptibility to DTIC in five different melanoma cell lines, one normal melanocyte line, and normal primary melanocytes. Results: Of the ninety-eight differentially expressed miRs, informatics predicted twelve putative tumor suppressor and five putative oncogene microRNAs, as well as one putative oncogenic microRNA cluster (miR-506-514 cluster; presented in a separate abstract by Streicher et al). Subsets of these miRs showed potent statistically significant effects in at least three malignant melanoma cell lines compared to normal melanocytes. Transfection of miR-126, -193b, -203 miR mimics or miR-146a or -21 miR inhibitors significantly increased caspase 3/7 activation in melanoma cell lines. MiR-126, -193b, or -206 miR mimics or miR-21 or -146a miR inhibitors significantly decreased tumor growth rate. Mir-193b, -206, -let7c miR mimics or miR-146a, -21, of -31 miR inhibitors decreased melanoma cell migration and invasion. None of the tested miRs showed an effect on susceptibility to dacarbazine. Conclusions: In summary, we functionally annotated eight differentially expressed miRs as functional oncogenes or tumor suppressors in malignant melanoma cell lines that represent potential targets for melanoma therapy and biomarkers.