Expression of β-F1-ATPase and mitochondrial transcription factor A and the change in mitochondrial DNA content in colorectal cancer: clinical data analysis and evidence from an in vitro study

Purpose: Mitochondria play an important role in regulating apoptosis and thus may be involved in tumor progression. This study was conducted to elucidate the role of mitochondrial dysfunction in colorectal cancer (CRC). Methods: Mitochondrial DNA (mtDNA) content was analyzed with real-time polymerase chain reaction in 153 CRC patients who had received surgery at the Taipei Veterans General Hospital from January 1999 to December 2000. The expression of mitochondrial transcription factor A (TFAM) and β-F1-ATPase were analyzed using immunohistochemistry. HCT116 cells were cultured in 1% O₂ for at least 20 passages. Mitochondrial biogenesis, ATP production, and the apoptotic response to 5-fluorouracil were analyzed in the derived cells. Results: Disease stage was associated with changes in mtDNA content (p < 0.001), expression of TFAM (p = 0.004), and/or β-F1-ATPase (p < 0.001). CRCs with low expression of TFAM or β-F1-ATPase had a lower mtDNA content. In the multivariate analysis, disease stage was the most significant prognostic factor [95% confidence interval (CI), 2.82-6.23], followed by β-F1-ATPase [95% CI, 1.10-4.10]. In patients receiving 5-FU based chemotherapy, the 5-year disease-free survival rate was only 27% in CRC patients with a low β-F1-ATPase tumor and was significantly lower than that in those with a high β-F1-ATPase tumor (60%; p = 0.042). In the hypoxia-treated cells, mitochondrial mass increased, mtDNA content decreased, sensitivity to 5-fluorouracil decreased, and β-F1-ATPase expression decreased. Conclusion: Mitochondrial dysfunction may be associated with poor outcomes in CRC patients.