Expression levels of FBXW7 and MDM2 E3 ubiquitin ligases and their c-Myc and p53 substrates in patients with dysplastic nevi or melanoma.

E3 ubiquitin ligases are of interest as drug targets due to their involvement in the regulation of the functions and interactions of several proteins. Various E3 ligase complexes are considered oncogenes or tumor suppressors associated with the development of melanoma. These proteins regulate the functions of various signaling pathways and proteins, such as p53 and Notch. The aim of the present study was to determine the expression levels of F-box and WD repeat domain-containing 7 (FBXW7), c-Myc, MDM2 and p53 proteins in samples from patients with dysplastic nevi or melanoma, and to evaluate their association with clinicopathological parameters and prognosis of the disease. Paraffin blocks with postoperative material from 100 patients diagnosed with dysplastic moles or melanoma were used in the present study. Tissue microarrays and immunohistochemistry were used to examine FBXW7, c-Myc, MDM2 and p53 protein expression. The results revealed that there was significantly lower FBXW7 expression in advanced melanoma compared with dysplastic nevus, melanoma in situ and stage pT1 melanoma (P<0.001). Additionally, there was a statistically significant association between the expression levels of FBXW7 and the morphological type of the tumor (P<0.001). In addition, there was a strong positive association between FBXW7 expression and the changes in c-Myc expression (P<0.02), and a strong trend was observed between decreased FBXW7 expression and a higher risk of death in patients, with the major factor in patient mortality being the stages of melanoma. Additionally, p53 expression was associated with the depth of melanoma invasion and the morphological type of the tumor. In summary, FBXW7 expression exhibited the highest statistically significant prognostic value and associations with advanced melanoma. As the majority of FBXW7 substrates are oncoproteins, their degradation by FBXW7 may highlight these proteins as potential targets for the treatment of melanoma.

Analysis of prognostic factors for melanoma patients.

Introduction. Melanoma is the most dangerous form of skin cancer. Morbidity from melanoma is increasing every year. Previous studies have revealed that there are some demographic and clinical factors having effect on melanoma survival prognosis. Aim of the study. Purpose of our study was to assess melanoma survival depending on prognostic factors, such as age, sex, stage, depth, histology and anatomical site. Materials and methods. We investigated melanoma-specific survival up to 10 years in 85 primary cases of melanoma from diagnosis at the National Cancer Institute in 2006. Analysis was performed for one-, five-, and ten-year survival. The data were processed with Microsoft Excel, data analysis was conducted using SPSS® software. Results. Melanomas diagnosed at stage IV or thicker than 4.00 mm had lower survival (five-year survival: 12.5% and 26.66%, respectively). A significant survival difference was observed among the different stages (p = 0.003) and different depths (p = 0.049) of melanoma. Ten-year survival was 32% for men and 61% for women, but melanoma-specific survival dependent on sex did not have a statistically significant difference (p = 0.121). In persons diagnosed at the age of 65 or older, ten-year survival was lower than in those of 40-64 years of age and in the age group of 15-39 years (44.44% and 26.66%, respectively), but melanoma-specific survival in different age groups did not have a statistically significant difference (p = 0.455). Back/breast skin melanoma had lower ten-year survival (37.03%) than other anatomic sites. Nodular melanoma had the poorest five-year and ten-year melanoma-specific survival among histological subtypes (51.67% and 38.75%). The differences between melanoma localizations (p = 0.457) and histological types (p = 0.364) were not statistically significant. Conclusions. Lower melanoma-specific survival rates were observed among patients diagnosed at a late stage, older age, and when melanomas were thicker than 4.00 mm. Female and younger patients had better melanoma-specific survival than men and older people, and these differences were statistically significant. Melanoma diagnosed at an early stage and of a small depth had higher survival rates. Back/breast skin melanoma had poorer prognosis than other anatomic sites. Nodular melanoma had the lowest melanoma-specific survival, while superficial spreading or lentigo maligna had the best prognosis among histological subtypes. However, differences in melanoma survival in different sex and age groups, localizations and histological types were not statistically significant.

E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma.

Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.

Molecular alterations in signal pathways of melanoma and new personalized treatment strategies: Targeting of Notch.

Despite modern achievements in therapy of malignant melanomas new treatment strategies are welcomed in clinics for survival of patients. Now it is supposed that personalized molecular therapies for each patient are needed concerning a specificity of molecular alterations in patient's tumors. In human melanoma, Notch signaling interacts with other pathways, including MAPK, PI3K-AKT, NF-kB, and p53. This article discusses mutated genes and leading aberrant signal pathways in human melanoma which are of interest concerning to their perspective for personalized treatment strategies in melanoma. We speculate that E3 ubiquitin ligases MDM2 and MDM4 can be attractive therapeutic target for p53 and Notch signaling pathways in malignant melanoma by using small molecule inhibitors. It is possible that restoration of p53-MDM2-NUMB complexes in melanoma can restore wild type p53 function and positively modulate Notch pathway. In this review we summarize recent data about novel US Food and Drug Administration approved target drugs for metastatic melanoma treatment, and suppose model for treatment strategy by targeting Notch.