Cytoplasmic Skp2 Expression Is Increased in Human Melanoma and Correlated with Patient Survival

Abstract

BackgroundS-phase kinase protein 2 (Skp2), an F-box protein, targets cell cycle regulators via ubiquitin-mediated degradation. Skp2 is frequently overexpressed in a variety of cancers and associated with patient survival. In melanoma, however, the prognostic significance of subcellular Skp2 expression remains controversial.MethodsTo investigate the role of Skp2 in melanoma development, we constructed tissue microarrays and examined Skp2 expression in melanocytic lesions at different stages, including 30 normal nevi, 61 dysplastic nevi, 290 primary melanomas and 146 metastatic melanomas. The TMA was assessed for cytoplasmic and nuclear Skp2 expression by immunohistochemistry. The Kaplan-Meier method was used to evaluate the patient survival. The univariate and multivariate Cox regression models were performed to estimate the harzard ratios (HR) at five-year follow-up.ResultsCytoplasmic but not nuclear Skp2 expression was gradually increased from normal nevi, dysplastic nevi, primary melanomas to metastatic melanomas. Cytoplasmic Skp2 expression correlated with AJCC stages (I vs II–IV, P<0.001), tumor thickness (≤2.00 vs >2.00 mm, P<0.001) and ulceration (P = 0.005). Increased cytoplasmic Skp2 expression was associated with a poor five-year disease-specific survival of patients with primary melanoma (P = 0.018) but not metastatic melanoma (P>0.05).ConclusionThis study demonstrates that cytoplasmic Skp2 plays an important role in melanoma pathogenesis and its expression correlates with patient survival. Our data indicate that cytoplasmic Skp2 may serve as a potential biomarker for melanoma progression and a therapeutic target for this disease.

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

“…Consistently, upregulation of Skp2 in mice enhanced tumor growth in lymphoma (21), prostate cancer (19) and breast tumor (18). Importantly, high expression of Skp2 has been observed in a wider spectrum of cancers including lymphomas (22,23) (25)(26)(27)(28)(29), prostate (30,31) and gastric cancer (32), melanoma (33)(34)(35), hepatocarcinoma (36) and nasopharyngeal carcinoma (37,38). Skp2 was also highly expressed and was correlated with relapse, metastasis and survival in OS patients (39).…”

Decreased Expression of Nuclear p300 Is Associated with Disease Progression and Worse Prognosis of Melanoma Patients

“…The use of human skin tissues and the waiver of patient consent in this study were approved by the Clinical Research Ethics Board of the University of British Columbia [15]. The study was conducted according to the principles expressed in the Declaration of Helsinki.…”

Recent advances in SCF ubiquitin ligase complex: Clinical implications

“…On the other hands, overexpression of Skp2 in mice led to tumor development including lymphoma [116], prostate cancer [114], mammary gland tumor [113]. Consistently, overexpression of Skp2 has been frequently observed in a variety of human cancers such as lymphomas [117, 118], pancreatic cancer [119], breast carcinomas [120-124], prostate cancer [125, 126], melanoma [127-129], and nasopharyngeal carcinoma [130, 131]. Importantly, Skp2 expression is associated with histological grade and tumor size in hepatocarcinoma [132].…”