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

Abstract

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively modified lesions in DNA. Our previous study (Kondo et al, Free Radic. Biol. Med., 27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively stressed based on 8-OHdG determination. To elucidate 8-OHdG metabolism and its clinical significance in colorectal carcinoma, we studied the 8-OHdG repair system in DNA by measuring specific lyase activity and hOGG1 expression using quantitative-competitive reverse transcription-PCR. In addition, we searched for the presence of mutations and single nucleotide polymorphisms of the hOGG1 gene by single-strand conformational polymorphism and sequencing analyses. It was found that 8-OHdG-specific lyase activity and hOGG1 expression were significantly up-regulated in carcinoma, and a proportional association between 8-OHdG levels and either 8-OHdG lyase activity (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 early- and advanced-stage cancer, lyase activity (1.2-fold) and hOG1 expression (1.6-fold) were significantly increased in advanced-stage cancer. No mutation was found in the 25 tumors examined. Three kinds of single nucleotide polymor. phism 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 that increased 8-OHdG levels in colorectal carcinoma are attributed to increased formation and are maintained by induced 8-OHdG repair activity at appropriate high levels. Our results may offer a unique approach in the development of preventive and therapeutic interventions as well as new insights into the pathogenesis of colorectal carcinoma.

• Authors: S Kondo, S Toyokuni, T Tanaka, H Hiai, H Onodera, H Kasai, M Imamura
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 4 Pg. 1394-400 (Apr 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10778969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm
• RNA, Messenger
• RNA, Neoplasm
• 8-Hydroxy-2'-Deoxyguanosine
• Deoxyribonuclease IV (Phage T4-Induced)
• N-Glycosyl Hydrolases
• DNA-Formamidopyrimidine Glycosylase
• Carbon-Oxygen Lyases
• DNA-(Apurinic or Apyrimidinic Site) Lyase
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Carbon-Oxygen Lyases (metabolism)
• Chromatography, High Pressure Liquid
• Colorectal Neoplasms (enzymology, genetics)
• DNA Mutational Analysis
• DNA, Neoplasm (genetics, metabolism)
• DNA-(Apurinic or Apyrimidinic Site) Lyase
• DNA-Formamidopyrimidine Glycosylase
• Deoxyguanosine (analogs & derivatives, metabolism)
• Deoxyribonuclease IV (Phage T4-Induced)
• Gene Expression Regulation, Neoplastic
• Humans
• N-Glycosyl Hydrolases (genetics)
• Polymorphism, Single Nucleotide
• Polymorphism, Single-Stranded Conformational
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics)
• Reverse Transcriptase Polymerase Chain Reaction (methods)