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

Julija Mozuraitiene; Zivile Gudleviciene; Ieva Vincerzevskiene; Aida Laurinaviciene; Justinas Pamedys

doi:10.3892/ol.2020.12298

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

Oncol Lett. 2021 Jan;21(1):37. doi: 10.3892/ol.2020.12298. Epub 2020 Nov 12.

Authors

Julija Mozuraitiene^{1

2}, Zivile Gudleviciene³, Ieva Vincerzevskiene^{4

5}, Aida Laurinaviciene^{6

7}, Justinas Pamedys⁷

Affiliations

¹ Outpatient Clinic, National Cancer Institute, LT-08660 Vilnius, Lithuania.
² Clinic of Internal Diseases, Family Medicine and Oncology, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania.
³ Biobank, LT-08660 Vilnius, Lithuania.
⁴ Laboratory of Clinical Oncology, National Cancer Institute, LT-08660 Vilnius, Lithuania.
⁵ Institute of Biosciences, Vilnius University, LT-10257 Vilnius, Lithuania.
⁶ Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania.
⁷ National Center of Pathology Affiliated to Vilnius University Hospital SantarosKlinikos, LT-08406 Vilnius, Lithuania.

Abstract

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.

Keywords: F-box and WD repeat domain-containing 7; MDM2; c-Myc; melanoma; p53; prognostic factor; ubiquitin ligases.