Diagnostic value and prognostic significance of plasmatic proteasome level in patients with melanoma

Abstract

Plasmatic proteasome (p-proteasome) also called circulating proteasome has recently been described as a tumor marker. We investigated the diagnostic and prognostic accuracies of p-proteasome levels in a melanoma population classified according to the American Joint Committee on Cancer staging system. Using an ELISA test, we measured p-proteasome levels in 90 patients and 40 controls between March 2003 and March 2008. The subunit composition of p-proteasomes was determined in metastatic melanoma by proteomic analysis. The mean p-proteasome levels were correlated with stages (P < 0.0001; r(S) = 0.664). They were significantly higher in patients with stage IV and stage III with lymph node metastasis (9187 ± 1294 and 5091 ± 454 ng/ml, respectively) compared to controls (2535 ± 187 ng/ml; P < 0.001), to stage I/II (2864 ± 166 ng/ml; P < 0.001) and to stage III after curative lymphadenectomy (2859 ± 271 ng/ml; P < 0.001). The diagnostic accuracy of p-proteasome was evaluated by receiver operating characteristic analysis. With a cut-off of 4300 ng/ml, diagnostic specificity and sensitivity of p-proteasome for regional or visceral metastases were respectively 96.3% and 72.2%. In univariate analysis, high p-proteasome levels (>4300 ng/ml) were significantly correlated with an increased risk of progression [hazard ratio (HR) = 7.34; 95% CI 3.54-15.21, P < 0.0001] and a risk of death (HR = 5.92; 95% CI 2.84-12.33, P < 0.0001). In multivariate analysis, high p-proteasome levels were correlated with a poorer clinical outcome in the subgroup analysis limited to patients with disease stages I, II and III. Proteomic analysis confirmed the presence of all proteasome and immunoproteasome subunits. Taken together, these results indicate that p-proteasomes are a new marker for metastatic dissemination in patients with melanoma.

Increased plasma proteasome chymotrypsin-like activity in patients with advanced solid tumors

“…Significantly elevated plasma proteasome concentrations were reported in a group of 20 patients with different epithelial solid tumors (breast, renal, gastric, kidney, colon, testicle, or lung) [25] and more recently in a large cohort of 120 patients with newly diagnosed epithelial ovarian cancer employing ELISA-based assay [29]. In addition, data from a study conducted in patients with malignant melanoma demonstrated significantly elevated circulating proteasome concentration in stages III/IV vs. stages I/II [27,28]. It is worth of note that in stage I/II malignant melanoma patients, plasma proteasome concentration was not significantly different from that observed in normal volunteers [27].…”

“…So far, circulating proteasome has been detected in patients with solid tumors using the ELISA test employing antibodies directed against the constitutive α subunits of the 20S proteasome [25][26][27][28][29][30]. However, ELISA-based assay Fig.…”

Lecithin retinol acyltransferase as a potential prognostic marker for malignant melanoma

“…Besides morphological and histopathological markers, several molecular markers have diagnostic and prognostic utility (1). These include markers on the melanoma, for example methylthioadenosine phosphorylase (MTAP) (2), nestin and SOX9 (3), and markers in patients' blood, for example p-proteasome levels (4). The search for a prognostic marker continues, however.…”

Involvement of the ubiquitin‐proteasome system in the stabilization of cell–cell contacts in human keratinocytes

“…Data are presented as means ± SD. *P < 0.05; **P < 0.001. novel strategies for several diseases including cancer progression and cystic fibrosis (8,(20)(21)(22)(23)(24). Here, we provide evidence for the first time that the inhibition of the UPS increases the stabilization of cell-cell contacts in human keratinocytes, which might be mediated by the maintenance of DP at desmosomes.…”