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Oncogene c-Myc-dependent pathways in cutaneous melanoma03

Mikhail Nikiforov

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National Institutes of Health (NIH)
Malignant melanoma is one of the most aggressive types of human cancer. Its ability to metastasize makes melanoma extremely difficult to cure, and consequently, the median survival of patients with metastatic melanoma is only 8.5 months. The molecular mechanisms underlying melanoma development are not well understood, and reliable markers associated with specific stages of melanoma progression are yet to be determined. Activating amino acid substitutions in oncoproteins BRAF (V600E) and NRAS (Q61R) have been found in approximately 60% and 20% of melanomas, respectively. Intriguingly, the same mutations were found at even higher frequencies in samples from benign human nevi (aggregation of normal melanocytes). In cultured normal human melanocytes, BRAFV600E or NRASQ61R induce senescence phenotypes that are virtually identical to those observed in nevi. Thus, melanomas originating from nevi must have developed mechanisms to overcome oncogene-induced senescence (OIS), but the nature of such mechanisms is largely unknown. We have recently demonstrated that unlike mouse or human fibroblasts, depletion of p53 or p16INK4A tumor suppressors is not sufficient to overcome OIS in human melanocytes. Instead, we have demonstrated that ectopic expression of oncoprotein C-MYC significantly suppressed BRAFV600E- and, less efficiently, NRASQ61R- induced senescence in these cells. Moreover, we demonstrated for the first time that depletion of C-MYC in human metastatic melanoma cells re-activated dormant BRAFV600E- or NRASQ61-specific senescence programs, thus indicating that C-MYC is required for continuous suppression of OIS during melanoma progression. C-MYC is a transcription factor that regulates the expression of multiple genes involved in many cellular processes. It is overexpressed in the vast majority of human malignancies, including melanoma. The mechanisms by which C-MYC suppresses OIS or RS in normal human melanocytes or keeps senescence programs dormant in human melanoma cells remain unknown. We also address the mechanism underlying melanoma invasiveness, one of its most detrimental features. C-MYC has been implicated in the induction of invasiveness in tumor cells, although the mechanisms are not known. In the past cycle of support, we confirmed the role of C-MYC in promoting melanoma invasiveness. Also, we have identified previously unknown functions for the rate-limiting enzymes involved in the metabolism of nucleotides. We found that several of such enzymes (encoded by C-MYC-dependent genes) suppress senescence-like phenotypes while others regulate melanoma cell invasiveness. The proposed research will establish the mechanisms by which C-MYC-dependent nucleotide biosynthesis controls OIS in melanocytic cells and invasiveness in melanoma cells. Our findings have broad scientific appeal since the suppression of OIS is a prerequisite for tumorigenesis including melanomagenesis, and invasiveness is a key condition for the development of metastases which is the most detrimental stage of cancer. The field of melanoma research is in need of reliable markers associated with specific stages of the disease progression. Our preliminary data indicate that C-MYC is a likely independent prognostic factor for overall survival (OS) in primary melanoma patients. Therefore, we will determine OS prognostic values of C- MYC separately and in conjunction with several C-MYC targets for patients with primary melanomas and nodal melanoma metastases.

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