Prognostic Significance of Nuclear ING3 Expression in Human Cutaneous Melanoma

Abstract

Purpose:The novel tumor-suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. Our previous study showed that ING3 promotes UV-induced apoptosis via the Fas/caspase-8^dependent pathway in melanoma cells. To investigate the putative role of ING3 in the development of melanoma, we examined the expression of ING3 in melanocytic lesions at different stages and analyzed the correlation between ING3 expression and clinicopathologic variables and patient survival. Experimental Design: Using tissue microarray and immunohistochemistry, we evaluated nuclear and cytoplasmic ING3 staining in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas. Results: Nuclear ING3 expression was remarkably reduced in malignant melanomas compared with dysplastic nevi (P < 0.001), which was significantly correlated with the increased ING3 level in cytoplasm (P < 0.05). Furthermore, the reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of patients with primary melanoma, especially for the high-risk melanomas (thickness z2.0 mm) with the survival rate reducing from 93% for patients with strong nuclear ING3 staining in their tumor biopsies to 44% for those with negative-to-moderate nuclear ING3 staining (P = 0.004). Strikingly, our multivariate Cox regression analysis revealed that reduced nuclear ING3 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.038). Conclusions: Our data indicate that ING3 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target.

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

“…In HNSCCs, the ING3 gene is rarely mutated, but 50% of primary HNSCCs has decreased or no expression of ING3 mRNA because of loss of heterozygosity (Gunduz et al, 2002(Gunduz et al, , 2008. In this study, we found that rapid ING3 degradation has an important role in the loss of ING3 expression in advanced melanomas, thereby providing another explanation of aberrant ING3 expression in melanomas in addition to our previous finding that subcellular relocalization of ING3 causes its deregulation in both primary and metastatic melanomas (Wang et al, 2007). Meanwhile, ING1b has been shown to be shifted from the nucleus to the cytoplasm in melanocytic lesions (Nouman et al, 2002), which may be mediated by 14-3-3 proteins (Gong et al, 2006).…”

“…Stabilization of ING3 protein in the metastatic MMRU melanoma cells resulted in enhanced tumorsuppressive functions of ING3 (Figure 6), which provides possible explanation for our previous finding that reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of melanoma patients (Wang et al, 2007). Although ING3 has been reported to inhibit growth and promote apoptosis in RKO cells (Nagashima et al, 2003), the mechanism of inhibitory effect of ING3 in melanoma progression and metastasis is unclear.…”

“…Recent studies by our group and Gunduz et al suggest that ING3 is deregulated and functions as a tumor suppressor in both melanomas and HNSCCs (Gunduz et al, 2002(Gunduz et al, , 2008Wang and Li, 2006;Wang et al, 2007). However, the mechanisms causing distorted ING3 expression in melanomas are different from that in HNSCCs.…”

“…In melanoma cells, we have shown that ING3 promotes ultraviolet (UV)-induced apoptosis through the Fas/caspase-8-dependent pathway (Wang and Li, 2006). We have also shown in a tissue microarray study that nuclear ING3 expression is remarkably reduced in malignant melanomas compared with dysplastic nevi, and the reduced nuclear ING3 level significantly correlates with a poorer diseasespecific 5-year survival of patients with primary melanoma (Wang et al, 2007). However, the mechanism resulting in aberrant ING3 expression in melanomas is not clear.…”

Biomarkers for Melanoma Diagnosis and the Technologies Used to Identify Them

“…This technique is suitable for the validation of candidate biomarkers, which are first obtained by other proteomics techniques. Several biomarkers of melanoma such as HSP 90 (McCarthy et al, 2008), ING3 (Wang et al, 2007), and the epidermal growth factor receptor family member HER3 (Reschke et al, 2008) were validated using this technique. For comprehensive screening of biomarkers from lysates collected from tumor tissue and cultured cells, 2-DE combining MS is used as a standard method.…”