Published online Oct 28, 2013. doi: 10.3748/wjg.v19.i40.6894
Revised: September 4, 2013
Accepted: September 15, 2013
Published online: October 28, 2013
Processing time: 186 Days and 21.3 Hours
AIM: To determine the expression of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and the Ku70/Ku80 heterodimer (Ku 70/80) in gastric carcinoma.
METHODS: Gastric biopsies were obtained from 146 gastric carcinoma patients [Helicobacter pylori (H. pylori)-negative: 89 and H. pylori-positive: 57] and 34 from normal subjects (H. pylori-negative: 16 and H. pylori-positive: 18) via surgery and endoscopic detection from April 2011 to August 2012 at the First Affiliated Hospital of Nanchang University. Pathological diagnosis and classification were made according to the criteria of the World Health Organization and the updated Sydney system. An ‘‘in-house’’ rapid urease test and modified Giemsa staining were employed to detect H. pylori infection. The expression of DNA-PKcs and the Ku 70/80 protein was detected by immunohistochemistry.
RESULTS: Overall, the positive rates of both DNA-PKcs and Ku 70/80 were significantly increased in gastric cancer (χ2 = 133.04, P < 0.001 for DNA-PKcs and χ2 = 13.06, P < 0.01 for Ku) compared with normal gastric mucosa. There was hardly any detectable expression of DNA-PKcs in normal gastric mucosa, and the positive rate of DNA-PKcs protein expression in patients with a normal gastric mucosa was 0% (0/34), whereas the rate in gastric cancer (GC) was 93.8% (137/146). The difference between the two groups was statistically significant. Additionally, the positive rate of Ku 70/80 was 79.4% (27/34) in normal gastric mucosa and 96.6% (141/146) in gastric cancer. The DNA-PKcs protein level was significantly increased in gastric cancer (Mann-Whitney U = 39.00, P < 0.001), compared with normal gastric mucosa. In addition, there was a significant difference in the expression of Ku 70/80 (Mann-Whitney U = 1117.00, P < 0.001) between gastric cancer and normal gastric mucosa. There was also a significant difference in Ku70/80 protein expression between GC patients with and without H. pylori infection (P < 0.05). Spearman analysis showed a negative correlation between tumor differentiation and DNA-PKcs expression (r = -0.447, P < 0.05). Moreover, Ku70/80 expression was negatively correlated with both clinical stage (r = -0.189, P < 0.05) and H. pylori colonization (r = -0.168, P < 0.05).
CONCLUSION: Overall, this research demonstrated that enhanced DNA-PKcs and Ku 70/80 expression may be closely associated with gastric carcinoma.
Core tip: This is the first study to clarify the two key promoters of the non-homologous end joining (NHEJ) pathway, DNA-dependent protein kinase (DNA-PKcs) and Ku 70/80, in human gastric carcinoma tissues. The present study found an upregulated expression of DNA-PKcs and Ku 70/80 in gastric cancer tissues compared with normal gastric mucosa, which suggests that there is an enhanced function of NHEJ in gastric carcinogenesis. As NHEJ is an error-prone and non-specific repair mechanism and can be induced before homologous recombination, its excessive activation is capable of regulating cell cycle arrest, cell apoptosis, chromosome recombination and genome instability.