Nuclear oxidative damage correlates with poor survival in colorectal cancer.
Oxidative DNA damage results from DNA adducts such as 8-oxo-7, 8 dihydro-2'-deoxyguanosine (8-oxo-dG), which is a pro-mutagenic lesion. No known association between 8-oxo-dG, disease progression and survival exists in colorectal cancer (CRC). We examined levels of 8-oxo-dG in sporadic CRC to determine its relationship with pathological stage and outcome. A total of 143 CRC patients and 105 non-cancer patients were studied. Nuclear and cytoplasmic 8-oxo-dG was assessed using immunohistochemistry. Double immunofluorescence using 8-oxo-dG and manganese superoxide dismutase (MnSOD) antibodies localised cytoplasmic 8-oxo-dG. Apoptosis was detected using TUNEL. Nuclear staining levels were similar in tumour tissue and matched normal mucosa in both epithelial (P=0.22) and stromal (P=0.85) cells. Epithelial cytoplasmic staining was greater in tumour tissue (P<0.001). Double immunofluorescence localised cytoplasmic 8-oxo-dG to mitochondria. Epithelial and stromal nuclear 8-oxo-dG decreased with local disease spread, but highest levels were found in distant disease (P<0.01). Survival was related to epithelial nuclear and stromal staining in normal mucosa (P<0.001) and tumour (P<0.01) but was unrelated to cytoplasmic staining. Normal control cells in tissue from cancer patients with high levels of 8-oxo-dG failed to undergo cell death. 8-oxo-dG may be an important biomarker of disease risk, progression and survival for CRC patients.
Sheridan
J
J
Centre for Colorectal Disease, St Vincent's University Hospital, Elm Park Dublin 4, Republic of Ireland.
Wang
L-M
LM
Tosetto
M
M
Sheahan
K
K
Hyland
J
J
Fennelly
D
D
O'Donoghue
D
D
Mulcahy
H
H
O'Sullivan
J
J
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D015996:Survival Rate; D046888:Tissue Array Analysis; D055815:Young Adult
D014408:Biomarkers, Tumor; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D003849:Deoxyguanosine