Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma

Abstract

Somatic mutations in mitochondrial DNA (mtDNA) have been detected in hepatocellular carcinoma (HCC). However, it remains unclear whether mtDNA copy number and mitochondrial biogenesis are altered in HCC. In this study, we found that mtDNA copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with the corresponding nontumorous livers. MtDNA copy number was significantly reduced in female HCC but not in male HCC. Expression of the peroxisome proliferator-activated receptor g coactivator-1 was significantly repressed in HCCs (Po0.005), while the expression of the mitochondrial single-strand DNA-binding protein was upregulated, indicating that the regulation of mitochondria biogenesis is disturbed in HCC. Moreover, 22% of HCCs carried a somatic mutation in the mtDNA D-loop region. The non-tumorous liver of the HCC patients with a long-term alcohol-drinking history contained reduced mtDNA copy number (Po0.05) and higher level of the 4977 bp-deleted mtDNA (Po0.05) as compared with non-alcohol patients. Our results suggest that reduced mtDNA copy number, impaired mitochondrial biogenesis and somatic mutations in mtDNA are important events during carcinogenesis of HCC, and the differential alterations in mtDNA of male and female HCC may contribute to the differences in the clinical manifestation between female and male HCC patients.

Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases

“…A significant increased proportion of the mtDNA 4977 mutation has been reported in various type of cancer, including nasopharyngeal, esophageal cancer, stomach, thyroid, salivary glands, hepatocellular and oral cancers (5,18,(25)(26)(27)(28). However, in more recent studies, a decreased proportion of the mtDNA 4977 mutation in tumor tissue as compared with corresponding non-tumorous tissue has been observed in gastric, hepatocellular, oral, and skin cancers (29)(30)(31)(32). This phenomenon has been explained as being either the result of a dilution effect due to rapid cytoplasmic division or from the result of a selective effect via an unknown mechanism by which cancer cells harboring mtDNA with the large-scale deletion are eliminated because of apoptosis or selective purification during growth (30).…”

Mitochondrial DNA content in paired normal and cancerous breast tissue samples from patients with breast cancer

“…Decrease of mtDNA has been observed in renal cancer (Meierhofer et al 2004) and hepatocellular carcinoma (Yin et al 2004). However, the pathogenesis of mtDNA decrease in cancers remains unclear.…”

“…Quantitative aberrations of mtDNA have been observed in various sample types from patients with cancers (Mambo et al 2005). While increased mtDNA content has been found in prostate (Mizumachi et al 2008a), head and neck (Kim et al 2004), endometrial adenocarcinoma (Wang et al 2005), etc., reduced mtDNA content in renal (Meierhofer et al 2004) and liver cancers (Yin et al 2004) has been reported.…”

Regulation of mitochondrial DNA content and cancer

“…Several reports showed that mutations of mtDNA have been identified in various types of cancer including breast cancer, colon carcinoma, prostate cancer, pancreatic cancer, and others (Carew and Huang, 2002). Decrease for mtDNA in renal cancer (Selvanayagam and Rajaraman, 1996), hepatocellular carcinoma Yin et al, 2004) and gastric cancer (Wu et al, 2005) has also been reported. Additionally, Simonnet et al showed that a decrease in mitochondrial respiratory function was observed in accordance with increased invasiveness of cancer (Simonnet et al, 2002).…”