Mozuraitiene Julija, Gudleviciene Zivile, Vincerzevskiene Ieva, Laurinaviciene Aida, Pamedys Justinas
Outpatient Clinic, National Cancer Institute, LT-08660 Vilnius, Lithuania.
Clinic of Internal Diseases, Family Medicine and Oncology, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania.
Oncol Lett. 2021 Jan;21(1):37. doi: 10.3892/ol.2020.12298. Epub 2020 Nov 12.
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 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.
E3泛素连接酶因其参与多种蛋白质功能和相互作用的调节而成为有吸引力的药物靶点。各种E3连接酶复合物被认为是与黑色素瘤发生发展相关的癌基因或肿瘤抑制因子。这些蛋白质调节各种信号通路和蛋白质的功能，如p53和Notch。本研究的目的是确定发育异常痣或黑色素瘤患者样本中含F-盒和WD重复结构域7（FBXW7）、c-Myc、MDM2和p53蛋白的表达水平，并评估它们与疾病临床病理参数及预后的关系。本研究使用了100例诊断为发育异常痣或黑色素瘤患者的术后石蜡块。采用组织芯片和免疫组化检测FBXW7、c-Myc、MDM2和p53蛋白表达。结果显示，与发育异常痣、黑色素瘤和pT1期黑色素瘤相比，晚期黑色素瘤中FBXW7表达显著降低（P<0.001）。此外，FBXW7表达水平与肿瘤形态学类型之间存在统计学显著关联（P<0.001）。此外，FBXW7表达与c-Myc表达变化之间存在强正相关（P<0.02），观察到FBXW7表达降低与患者死亡风险增加之间有强烈趋势，黑色素瘤分期是患者死亡的主要因素。此外，p53表达与黑色素瘤浸润深度和肿瘤形态学类型相关。总之，FBXW7表达显示出与晚期黑色素瘤最高的统计学显著预后价值和关联。由于FBXW7的大多数底物是癌蛋白，它们被FBXW7降解可能突出这些蛋白作为黑色素瘤治疗的潜在靶点。
