Differential Expression of DNA Nonhomologous End-Joining Proteins Ku70 and Ku80 in Melanoma Progression

Abstract

Ku70 and Ku80 heterodimers function as regulatory subunits of the DNA-dependent protein kinase and play a very important role in the repairing of DNA double-strand breaks. Although Ku70 is proposed as a candidate for a tumor suppressor gene, not many data are available on Ku70 and Ku80 expression in human tumors. The main aim of this study was to investigate the expression of Ku70 and Ku80 in the ultravioletinduced lesions-nevus cell nevi, lentigos maligna, and malignant melanomas. Nineteen nevus cell nevi, 23 lentigos maligna, 76 primary melanomas, and 31 melanoma metastases were stained immunohistochemically for the presence of Ku70 and Ku80 proteins. Ku70 and Ku80 expression was preserved in about 80% of nevi, 26% of lentigo maligna, 45% of primary melanomas, and 67% of melanoma metastases. Highly significant differences in Ku70 and Ku80 expression were found between nevi, lentigo maligna, and melanomas. In Cox regression, Ku70 and Ku80 were shown to be highly significant influences on patients' prognosis. Significant correlations between Ku70 and Ku80 expressions were found in nevi, lentigo maligna, and primary melanomas. These correlations were not more present in melanoma metastases. To summarize, earlier phases of melanoma progression seem to be connected with the loss of expression of Ku proteins. Metastatic spread is related to dysregulation of the Ku70 and Ku80 axis.

7B7: a novel antibody directed against the Ku70/Ku80 heterodimer blocks invasion in pancreatic and lung cancer cells

“…Conversely, it has been suggested that deficient expression or lack of Ku70/Ku80 may result in genomic instability leading to tumourogenesis [41]. Earlier phases of melanoma progression are associated with loss of expression of Ku70/Ku80, and the binding activity of Ku70/Ku80 was reported to be strongly reduced at the advanced tumour stage in breast and bladder tumours [42,43]. There are limited investigations focused on DNA repair proteins in pancreatic cancer.…”

Identification and cloning of genes displaying elevated expression as a consequence of metastatic progression in human melanoma cells by rapid subtraction hybridization

“…However, metastasis is a complex process characterized by subclonal evolution (Fidler, 2002). Indeed, recent studies in a clinical setting have shown that functional dysregulation of Ku70 and Ku80 seems to be of greater biological importance than the loss of expression in metastatic tumor spread (Korabiowska et al, 2002). The mechanism of this dysregulation is not known but might be due to a defect in heterodimerization of Ku proteins which has been shown to have physiological importance for efficient nuclear translocation of each Ku.…”

Epigenetic Inactivation of the Chromosomal Stability Control Genes BRCA1, BRCA2, and XRCC5 in Non–Small Cell Lung Cancer

“…Mutation carriers have a statistically increased risk of several other cancers [i.e., pancreatic and cervical cancers with BRCA1 (13) and prostate, pancreas, stomach, melanoma, lung, and bladder cancers with BRCA2 (14)]. Decreased protein expression of XRCC5 is also reported for melanoma, cervical, and colon cancers (15). Frequent LOH at the BRCA1, BRCA2, and XRCC5 has been observed in several sporadic cancers other than breast and ovary (i.e., tumors of the colon, pancreas, soft tissue, and lung; refs.…”