Overexpression of the hOGG1 gene and high 8-hydroxy-2 '-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism ofthe 8-OHdG level in DNA

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidativel y modified lesions in DNA. Our previous study (Kondo et al., Free Radic. Bi ol. Med., 27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively stressed based on 8-OHdG determination, To elucidate 8-OHd G metabolism and its clinical significance in colorectal carcinoma, me stud ied the 8-OHdG repair system in DNA by measuring specific lyase activity an d hOGG1 expression using quantitative-competitive reverse transcription-PCR . In addition, me searched for the presence of mutations and single nucleot ide polymorphisms of the hOGG1 gene by single-strand conformational polymor phism and sequencing analyses. It was found that 8-OHdG-specific lyase acti vity and hOGG1 expression mere significantly up-regulated in carcinoma, and a proportional association between 8-OHdG levels and either 8-OHdG lyase a ctivity (r = 0.641, P < 0.05) or hOGG1 expression (r = 0.702, P < 0.05) was present. Whereas no difference was detected in the 8-OHdG level between ea rly- and advanced-stage cancer, lyase activity (1.2-fold) and hOGG1 express ion (1.6-fold) mere significantly increased in advanced-stage cancer, No mu tation was found in the 25 tumors examined, Three kinds of single nucleotid e polymorphism were observed, including that of codon 326 (Ser/Cys) in exon 7. However, there was no correlation between any of the three polymorphic patterns and either 8-OHdG level or lyase activity. These results suggest t hat increased 8-OHdG revels in colorectal carcinoma are attributed to incre ased formation and are maintained by induced 8-OHdG repair activity at appr opriate high levels. Our results may offer a unique approach in the develop ment of preventive and therapeutic interventions as well as new insights in to the pathogenesis of colorectal carcinoma.