A potential role of human DNA repair enzymes hMTH₁, hOGG₁ and hMYH_α in the hepatocarcinogenesis

Abstract

To elucidate role of the three enzymes in hepatocarcinogenesis, hMTH₁, hOGG₁ and hMYH, mRNA expression were examined by using RT/semi-quantitative real-time PCR and 8-O-HdG levels was studied by HPLC/ECD in HCC and non-tumorous liver tissue of 21 patients with hepatocellular carcinoma (HCC). It was found that the 8-OHdG level in non-tumourous liver tissue was significantly higher than in HCC tissue (P=0.006), and this was correlated with the degree of inflammation. The hMTH₁ expression in HCC tissue was significantly higher than in nontumorous liver tissue (P=0.014). Inversely, The hMYH_α expression was significantly increased (P=0.039) in non-tumorous liver tissue. No difference was seen in hOGG₁ expression in non-tumorous liver and HCC tissue. A significant linear correlation between hMTH₁ and hOGG₁ expression was found both in HCC tissue (r=0.809,P<0.001) and in non-tumorous liver tissue (r=0. 883,P<0.001). Our findings suggested a reactive rather than pathogenic role of the DNA repair enzymes in the hepatocarcinogenesis.

References

[1] ChengK C, CahillD S, KasaiH, et al.. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions. J Biol Chem, 1992, 267: 166-166

[2] FuruichiM, YoshidaM C, OdaH, et al.. Genomic structure and chromosome location of the human mutT homologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:G transversion. Genomics, 1994, 24: 485-485

[3] Van der KempP A, ThomasD, BarbeyR, et al.. Cloning and expression in Escherichia coli of the OGG1 gene of Saccharomyces cerevisiae, which codes for a DNA glycosylase that excises 7, 8-dihydro-8-oxoguanine and 2, 6-diamino-4-hydroxy-5-N-methylformamidopyrimidine. Proc Natl Acad Sci USA, 2002, 93: 5197-5197

[4] SlupskaM M, LutherW M, ChiangJ H, et al.. Functional expression of hMYHα a human homolog of the Escherichia coli MutY protein. J Bacteriol, 1999, 181: 6210-6210

[5] KnodellR G, IshakK G, BlackW C, et al.. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology, 1981, 1: 431-431

[6] GuptaR C. Nonrandom binding of the carcinogen N-hydroxy-2-acetylaminofluorene to repetitive sequences of rat liver DNA in vivo. Proc Natl Acad Sci USA, 1984, 81: 6943-6943

[7] ShimodaR, NagashimaM, SakamotoM, et al.. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res, 1994, 54: 3171-3171

[8] KennedyC H, CuetoR, BelinskyS A, et al.. Overexpression of hMTH₁ mRNA: a molecular marker of oxidative stress in lung cancer cells. FEBS Lett, 1998, 429: 17-17

[9] KondoS, ToyokuniS, TanakaT, et al.. 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. Clin Cancer Res, 2000, 6: 1394-1394

[10] ChevillardS, RadicellaJ P, LevaloisC, et al.. Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene, 1998, 16: 3083-3083

[11] SugimuraH, KohnoT, WakaiK, et al.. hOGG₁ Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 1999, 8: 669-669