Skp2 and p27kip1 expression in melanocytic nevi and melanoma:: an inverse relationship

Background: S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45(SKP2) is important in the degradation of p27(kip1) (a cyclin dependent kinase Inhibitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers. Methods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27(kip1) were investigated in 198 melanocytic proliferations: 2 1 melanocytic nevi, 2 3 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed. Results: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27(kip1), respectively, was identified moving from melanocytic nevi (0.05 +/- 0.2/85 +/- 15) to melanoma in situ (3 +/- 2/45 +/- 20) to primary cutaneous melanoma (12 +/- 9/ 30 +/- 25) to metastatic melanoma (25 +/- 15/15 +/- 20) (p less than or equal to 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (p less than or equal to 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = -0.4, p = 0.0001). Skp2 cytoplasmic labeling index of >20% predicted worse 10-year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis. Conclusions: Gain of Skp2 and loss of p27(kip1) protein expression are implicated in melanoma progression where the level of p27(kip1) may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.