PUMA expression is significantly reduced in human cutaneous melanomas

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 (Po0.0001), and is further reduced in metastatic melanomas compared to primary tumors (P ¼ 0.001). We show that weak PUMA expression in melanoma correlates with poorer overall and diseasespecific 5-year survival (Po0.005 and Po0.001, 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 ¼ 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.

Nuclear ING2 expression is reduced in human cutaneous melanomas

“…For example, the expression of proapoptotic factor Apaf-1, a p53 downstream effector, which links the release of cytochrome c to the activation of caspase-9, is reduced in human cutaneous melanomas compared with normal nevi (Dai et al, 2004). The expression of another p53 downstream effector PUMA is significantly reduced in melanoma compared to dysplastic nevi (Karst et al, 2005). Furthermore, the expression of proapototic protein XAF1, which blocks the XIAP-mediated inhibition of caspase-3 (Liston et al, 2001), is also reduced in human melanomas (Ng et al, 2004).…”

“…However, some factors are involved in more than one step in melanoma pathogenesis. For instance, although PUMA expression does not correlate with tumour thickness in primary melanoma, it is further reduced in metastatic melanoma and weaker PUMA expression is correlated with a poorer 5-year patient survival (Karst et al, 2005). Based on the complexity of the apoptotic and survival pathways which govern the fate of a cell, additional studies on the timing of the gene inactivation/overexpression in these pathways from the same set of tumour biopsies and the interdependence among these events will provide a more complete picture of the molecular changes during melanoma pathogenesis.…”

Role of the pro-survival molecule Bfl-1 in melanoma

“…In melanoma, a microarray analysis showed a decrease in Puma expression between non-malignant nevi and metastatic melanoma and these lower Puma expression levels correlated with poorer 5-year survival rates 299 . Although Puma loss has not been shown to cause cancer, knockdown of Puma expression mimics loss of p53 function in that it causes transformation of MEFs which already have activated E1A…”

Life in the balance: how BH3-only proteins induce apoptosis

“…Since the apoptosis elicited by E2F1 was reduced by downregulation of Puma or Noxa, their increased expression may represent a barrier to tumorigenesis. Pertinently, Puma expression is markedly reduced during melanoma progression [59].…”