Abstract
Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species (ROS), damaging DNA, RNA and free NTPs, and causing the accumulation of oxidative nucleic acids in cytoplasm. The major types are 8-oxo-7,8-dihydroguanine(8-oxoGsn) in RNA and 8-oxo-7,8-dihydro-2' deoxyguanosine(8-oxodGsn) in Mt-DNA. The MTH1 protein sanitizes oxidized nucleotide pools from NTPs to monophosphates, preventing the occurrence of transversion mutations. This study concerned cytoplasmic 8-oxodGsn/Gsn and MTH1 expression in gastric cancer and para-cancer tissues and elucidated roles of nucleic-acid oxidation and anti-oxidation. A polymer HRP detection system was used to detect 8-oxo-Gsn/dGsn and MTH1 expression in 51 gastric cancer and para-cancer tissue samples. Analyses of patient clinical and pathological data were also performed. The expression of MTH1 and the 8-oxo-dGsn/Gsn ratio were significantly higher in cancer tissues than para-cancer tissues (P<0.05). Cytoplasmic 8-oxo-Gsn and MTH1 were both found to positively correlate (P<0.05) with tumor differentiation, while no significant associations were found with gender, age, invasion depth, lymph node metastasis and clinical stage (P>0.05). We found 8-oxo-dGsn/Gsn and MTH1 are both highly expressed in gastric cancer tissues, especially in well differentiated lesions. In addition, oxidated mtDNA is prevalently expressed in gastric cancers, while 8-oxo-Gsn expression in cytoplasmic RNA is a bit lower, but more selectively.
Highlights
The accumulation of oxidative damage in nucleic acids is one of the major causes for mutagenesis and cell death (Nakabeppu et al, 2004)
Among the cytoplasmic oxidative nucleic acids, 8-oxo-7, 8-dihydroguanine (8-oxoGsn) of RNA and 8-oxo-7, 8-dihydro-2’deoxyguanosine (8-oxodGsn) of Mt-DNA are the major types, while oxidative NTP pools, such as 8-oxo-dGTP, which is a product of dGTP oxidation and can be inserted into opposite dA or dC residues of template DNA at almost identical efficiencies, causing G:C to T:A or T:A to G:C transversion mutations
8-Oxo-dGTP is a product of dGTP oxidation and can be inserted into opposite dA or dC residues of template DNA at almost identical efficiencies, so is the same as 8-oxo-GTP
Summary
The accumulation of oxidative damage in nucleic acids is one of the major causes for mutagenesis and cell death (Nakabeppu et al, 2004). Among the cytoplasmic oxidative nucleic acids, 8-oxo-7, 8-dihydroguanine (8-oxoGsn) of RNA and 8-oxo-7, 8-dihydro-2’deoxyguanosine (8-oxodGsn) of Mt-DNA are the major types, while oxidative NTP pools, such as 8-oxo-dGTP, which is a product of dGTP oxidation and can be inserted into opposite dA or dC residues of template DNA at almost identical efficiencies, causing G:C to T:A or T:A to G:C transversion mutations. Helge et al (2014) and Huber et al (2014) reported in nature that cancer cells required MTH1 activity to avoid incorporation of oxidized NTPs, resulting in nucleic-acid damage and cell death. Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species (ROS), damaging DNA, RNA and free NTPs, and causing the accumulation of oxidative nucleic acids in cytoplasm. This study concerned cytoplasmic 8-oxodGsn/Gsn and MTH1 expression in gastric cancer and para-cancer tissues and elucidated roles of nucleic-acid oxidation and anti-oxidation. Oxidated mtDNA is prevalently expressed in gastric cancers, while 8-oxo-Gsn expression in cytoplasmic RNA is a bit lower, but more selectively
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