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Quantitative, Real-time Analysis of Base Excision Repair Activity in Cell Lysates Utilizing Lesion-specific Molecular Beacons
Published on: August 6, 2012
Dysregulated Expression and Subcellular Localization of Base Excision Repair (BER) Pathway Enzymes in Gallbladder
Manoj Kumar1,2, Vijay Kumar Shukla3, Pravas Kumar Misra4
1Cytogenetics laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India.
Abstract:
Base excision repair (BER) pathway is one of the repair systems that has an impact on radiotherapy and chemotherapy for cancer patients. The molecular pathogenesis of gallbladder cancer is not known extensively. In the present study we investigated whether the expression of AP endonuclease 1 (APE1) and DNA polymerase β (DNA pol β), key enzymes of BER pathway has any clinical significance with gallbladder carcinogenesis. 41 gallbladder cancer, 27 chronic cholecystitis, and 3 normal gallbladder specimens were analyzed for the expression of APE1 and DNA polymerase β by western blotting, and subcellular localization studied by immunohistochemistry. The enzymatic activity of APE1 was also studied. The correlations with expression of the above proteins with clinical-pathological characteristics of gallbladder cancer patients were analyzed. The integrated density value ratio (relative expression) of total APE1 (37 kDa + 35 kDa variant) analyzed in the three groups of tissues, was 0.76±0.03 in normal gallbladder, 0.91±0.08 in chronic cholecystitis, and 1.12±0.05 in gallbladder cancer. APE1 was found to be up-regulated in 80% of gallbladder carcinoma samples (P = 0.01). A positive trend of APE1 expression with tumor stage and lymph node positivity was observed. The enzymatic activity of APE1 was found higher in gallbladder cancer samples in comparison with chronic cholecystitis. The integrated density value ratio of DNA polymerase β for normal gallbladder, chronic cholecystitis and gallbladder cancer tissue samples were 0.46±0.03, 0.7±0.06 and 1.33±0.1, respectively. DNA polymerase β was found to be upregulated in almost all gallbladder carcinoma samples (P =0.0001), and its expression was negatively correlated with age (P=0.02). DNA polymerase β expression showed a positive trend with tumor stage and nuclear differentiation of gallbladder cancer. It may be concluded that alteration of these BER pathway proteins may be the causal factors for carcinogenesis of gallbladder, and has targeted therapeutic potential.
Insights
Key enzymes in the Base Excision Repair (BER) pathway, AP endonuclease 1 (APE1) and DNA polymerase β (DNA pol β), are upregulated in gallbladder cancer. Their altered expression correlates with tumor progression, suggesting therapeutic potential.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- The molecular pathogenesis of gallbladder cancer remains incompletely understood.
- The Base Excision Repair (BER) pathway plays a crucial role in DNA repair and is implicated in cancer development and treatment response.
- Key BER enzymes, AP endonuclease 1 (APE1) and DNA polymerase β (DNA pol β), are critical for DNA repair efficiency.
Purpose of the Study:
- To investigate the clinical significance of APE1 and DNA pol β expression in gallbladder carcinogenesis.
- To determine the correlation between the expression of these BER enzymes and clinicopathological characteristics of gallbladder cancer patients.
Main Methods:
- Analysis of APE1 and DNA pol β expression in 41 gallbladder cancer, 27 chronic cholecystitis, and 3 normal gallbladder specimens using western blotting.
- Subcellular localization of APE1 and DNA pol β was assessed by immunohistochemistry.
- Enzymatic activity of APE1 was measured, and expression levels were correlated with clinical-pathological data.
Main Results:
- APE1 was upregulated in 80% of gallbladder cancer samples (P=0.01) and showed a positive trend with tumor stage and lymph node positivity.
- DNA polymerase β was upregulated in almost all gallbladder carcinoma samples (P=0.0001) and correlated positively with tumor stage and nuclear differentiation.
- APE1 enzymatic activity was higher in gallbladder cancer tissues compared to chronic cholecystitis.
Conclusions:
- Alterations in APE1 and DNA polymerase β expression are implicated in gallbladder carcinogenesis.
- These BER pathway proteins represent potential biomarkers and targeted therapeutic targets for gallbladder cancer.
- Further research into the role of BER in gallbladder cancer pathogenesis is warranted.
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