Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers

Kotake, Katsuhiro; Nonami, Toshiaki; Kurokawa, Tsuyoshi; Nakao, Akimasa; Murakami, Taro; Shimomura, Yoshiharu

doi:10.1016/s0024-3205(99)00117-4

Cited by 22 publications

(13 citation statements)

References 16 publications

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“…This is in apparent agreement with two previous studies, the first of which demonstrated a decrease in deletion frequency between normal, cirrhotic and tumour tissue (Kotake et al, 1999), and the second of which indicated a decrease in the deletion level in tumour compared to noncancerous in males but not females (Yin et al, 2004). In our cohort of patients who had tumours containing the deletion, all were male; however, as only seven of 62 of our subjects were female, it would be difficult to make comparisons between the sexes.…”

Section: Discussionsupporting

confidence: 93%

“…While mitochondrial mutations have been demonstrated in HCC, previous studies have been carried out on individuals with hepatitis C (Nishikawa et al, 2001;Lee et al, 2004;Kubo et al, 2003). The 4977 bp deletion is deleterious, affecting much of complex I of the electron transport chain, yet due to the number of mitochondria and multiple copies of mtDNA in each mitochondrion only 0.004% of liver mtDNA is thought to be affected in normal individuals (Kotake et al, 1999). The incidence of the 4977 bp deletion in liver increases with the age of subjects (Fukushima et al, 1995) and with chronic alcohol abuse (Mansouri et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…While increases in the frequency of the 4977 bp deletion have been demonstrated in tumours, the levels in HCC of subjects with HCV is thought to be reduced (Kotake et al, 1999).…”

mentioning

confidence: 99%

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Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver

et al. 2005

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The largest single underlying cause of hepatocellular carcinoma (HCC) worldwide is hepatitis B virus (HBV) infection. Hepatitis B virus increases cellular oxidative stress and the development of HCC occurs after a long latency period. The study was carried out to determine whether mitochondrial DNA abnormalities were associated with HCC in individuals with HBV. The frequency of mutation and deletion of specific areas of the mitochondrial genome in tumour and matched normal tissue of patients with HBV infection was investigated in the current study. The percentage of control subjects harbouring D-loop mutations was 11%, which was significantly lower than that observed in both the noncancerous (49%, P ¼ 0.033) and tumour tissue (59%, P ¼ 0.014) of patients with HCC. In contrast, the number of cases in which the common 4977 bp deletion of the mitochondrial genome was detected was significantly greater in control liver and noncancerous liver tissue of subjects with HCC (100 and 95%, respectively) than in cancerous liver tissue (28%, Po0.001). These observations suggest that the inflammatory process contributes to the rate of mitochondrial mutations. However, the lower frequency of the large deletion in cancerous tissue suggests that there is selection against either mitochondria, which harbour large deletions, or against cells that contain these mitochondria during hepatocarcinogenesis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver

et al. 2005

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“…Similarly, a slight decrease in the proportion of deleted mtDNA was also observed in the tumour tissues of the female HCC patients. Our results are in agreement with previous findings in HCC (Kotake et al, 1999) and in human oral cancers (Lee et al, 2001). Moreover, it was found that the proportion of mtDNA with deletion in the more rapidly dividing tissues was lower than that of tissues with a slow turnover rate (Kotake et al, 1999).…”

Section: Discussionsupporting

confidence: 93%

“…Our results are in agreement with previous findings in HCC (Kotake et al, 1999) and in human oral cancers (Lee et al, 2001). Moreover, it was found that the proportion of mtDNA with deletion in the more rapidly dividing tissues was lower than that of tissues with a slow turnover rate (Kotake et al, 1999). Thus, the decrease in the proportion of mtDNA with deletion in tumour tissues may have resulted from that the deleted mtDNA molecules were diluted in the HCC cells after high mitotic segregation.…”

Section: Discussionsupporting

confidence: 93%

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

Yin¹,

Lee

Chau³

et al. 2004

Br J Cancer

189

158

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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.

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Novel heteroplasmic frameshift and missense somatic mitochondrial DNA mutations in oral cancer of betel quid chewers

Chang

Chen

et al. 2003

Genes Chromosomes & Cancer

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Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis because of its high susceptibility to oxidative DNA damage and limited repair mechanisms. For investigation of the potential role of somatic mtDNA mutations in the tumorigenesis of oral cancer, we screened the occurrence of mtDNA mutations by the temporal temperature gradient gel electrophoresis method. We amplified the entire mitochondrial genome by use of 32 pairs of overlapping primers, and to identify the mutations, we sequenced DNA fragments showing different banding patterns between normal and tumor mtDNA. Fourteen of eighteen (77.8%) oral carcinomas displayed somatic mtDNA mutations, with a total of 26 mutations. Among them, six were in the mRNA coding region. Three were missense mutations (C14F, H186R, T173P) in NADH dehydrogenase subunit 2, and one was a frameshift mutation, 9485delC, in cytochrome c oxidase subunit III. Eight (44%) tumors had insertion or deletion mutations in the nucleotide position 303-309 poly C region of the D-loop. Multiple large deletions were also observed. Our results demonstrate that somatic mtDNA mutations occur in oral cancer. Some missense and frameshift mutations may play an important role in the tumorigenesis of this carcinoma. More extensive biochemical and molecular studies will be necessary for determining the pathologic effect of these somatic mutations.

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Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers

Cited by 22 publications

References 16 publications

Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver

Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver

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

Novel heteroplasmic frameshift and missense somatic mitochondrial DNA mutations in oral cancer of betel quid chewers

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