8-hydroxy-2--deoxyguanosine and Gallbladder-Neoplasms

Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Case-Control Studies; Cholecystitis; Cholelithiasis; DNA Glycosylases; DNA Methylation; DNA Repair; Female; Gallbladder; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; India; Male; Middle Aged; Neoplasm Invasiveness; Oxidative Stress; Polymorphism, Single Nucleotide; Prognosis; Promoter Regions, Genetic; Severity of Illness Index; Signal Transduction; X-ray Repair Cross Complementing Protein 1

Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases.. Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients.. Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057).. The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cholangiocarcinoma; DNA Damage; Female; Gallbladder Neoplasms; Guanine; Humans; Lymphatic Metastasis; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species

Pancreaticobiliary maljunction, an anomalous union of the pancreatic duct with the common bile duct, is a risk factor for biliary carcinoma. We hypothesized that, in patients with pancreaticobiliary maljunction, persistent regurgitation of pancreatic juice into the biliary tract induces oxidative DNA damage. We assessed the expression of an oxidative DNA base-modified product, 8-hydroxy-2'-deoxyguanosine, in gallbladder epithelium.. Eleven noncancerous gallbladders from patients with pancreaticobiliary maljunction, 12 gallbladder carcinomas from patients without pancreaticobiliary maljunction and 14 noncancerous gallbladders from patients without pancreaticobiliary maljunction (control) were studied.. Immunohistochemistry was performed for 4-hydroxy-2-nonenal-modified protein (as a marker for lipid peroxidation), 8-hydroxy-2'-deoxyguanosine and p53 gene product.. Stronger cytoplasmic staining of 4-hydroxy-2-nonenal-modified protein was observed in the gallbladder epithelium from patients with pancreaticobiliary maljunction than in epithelium from gallbladder cancer patients or from control subjects with normal gallbladders. Clear, strong nuclear staining of 8-hydroxy-2'-deoxyguanosine was observed in the gallbladder epithelial cells from patients with pancreaticobiliary maljunction. Densitometric quantitation revealed significantly higher expression of 8-hydroxy-2'-deoxyguanosine in gallbladder epithelial cells from patients with pancreaticobiliary maljunction (index 27.3 +/- 3.1) than in cells from patients with gallbladder carcinoma (11.4 +/- 1.5; P < 0.05) or from control subjects with normal gallbladder (6.4 +/- 1.0; P < 0.05). Positivity of p53 was 27% in gallbladder epithelium associated with pancreaticobiliary maljunction, 75% in gallbladder carcinoma epithelium and 0% in control epithelium.. These results suggest that reactive oxygen species are produced in the gallbladder of patients with pancreaticobiliary maljunction and that oxidative DNA injury is related to carcinogenesis in these patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Common Bile Duct; Deoxyguanosine; Epithelium; Female; Gallbladder; Gallbladder Neoplasms; Humans; Immunohistochemistry; Male; Middle Aged; Pancreatic Ducts; Tumor Suppressor Protein p53