Abstract
Cutaneous malignant melanoma is an aggressive form of skin cancer, characterized by strong chemoresistance and poor patient prognosis. The molecular mechanisms underlying its resistance to chemotherapy remain unclear but are speculated to involve the dysregulation of apoptotic pathways. In this study, we sought to determine whether PUMA (p53 upregulated modulator of apoptosis) contributes to human melanoma formation, tumor progression, and survival. We used tissue microarray and immunohistochemistry to examine PUMA expression in 107 primary melanomas, 51 metastatic melanomas, and 64 dysplastic nevi. Here we report that PUMA expression is significantly weaker in primary melanomas compared to dysplastic nevi (P<0.0001), and is further reduced in metastatic melanomas compared to primary tumors (P=0.001). We show that weak PUMA expression in melanoma correlates with poorer overall and disease-specific 5-year survival (P<0.005 and P<0.001, respectively) of melanoma patients and that PUMA expression in tumor tissue is an independent predictor of both overall and disease-specific 5-year survival (P=0.05). Additionally, we show that exogenous PUMA expression in human melanoma cell lines (both wild type and mutant p53) results in significant apoptotic cell death. Our results suggest that PUMA expression may be an important prognostic marker for human melanoma and that adenoviral delivery of PUMA sensitizes melanoma cells to apoptosis.
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Acknowledgements
We thank Nhu Le for his assistance with statistical analyses, David Huntsman and Nikita Makretsov for help in tissue microarray construction, and Andrew Coldman for collecting patient survival data. This work was supported by grants from the National Cancer Institute of Canada to GL. AK is supported by the Michael Smith Foundation for Health Research and by the Natural Sciences and Engineering Research Council of Canada. GL is a recipient of the Research Scientist Award from the National Cancer Institute of Canada supported with funds provided by the Canadian Cancer Society.
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Karst, A., Dai, D., Martinka, M. et al. PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene 24, 1111–1116 (2005). https://doi.org/10.1038/sj.onc.1208374
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DOI: https://doi.org/10.1038/sj.onc.1208374
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