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Lymphocytic mitochondrial DNA deletions, biochemical folate status and hepatocellular carcinoma susceptibility in a case–control study

  • Meng-Ying Wu (a1), Chang-Sheng Kuo (a1) (a2), Ching-Yih Lin (a3), Chin-Li Lu (a4) and Rwei-Fen Syu Huang (a1)...
Abstract

Mitochondrial (mt) DNA deletions and low folate status, proposed characteristics of carcinogenesis, in relation to human hepatocellular carcinoma (HCC) susceptibility are not clearly understood. We hypothesised that low folate status may modify frequencies of mtDNA deletions in humans, both of which could predispose individuals to HCC development. Biochemical folate status of serum and lymphocytes, and frequencies of mtDNA deletions in lymphocytes were determined in ninety HCC cases and ninety cancer-free healthy controls, individually matched by age and sex. The data revealed that HCC patients had lower levels of serum folate (P = 0·0002), lymphocytic folate (P = 0·040) and accumulated higher frequency of lymphocytic mtDNA deletions (P < 0·0001) than the controls. In the total studied subjects, frequencies of lymphocytic mtDNA deletions were associated with hepatitic B infection (P = 0·004) and HCC incidents (P = 0·001), and were correlated with serum folate (r − 0·155; P = 0·041), lymphocyte folate (r − 0·314; P = 0·0001), levels of glutamate-oxaloacetate transaminase (GOT) (r 0·206; P = 0·006), glutamate-pyruvate transaminase (GPT) (r 0·163; P = 0·037) and α-fetal protein concentrations (r 0·212; P = 0·005). After adjustment for age, sex, lifestyle and one-carbon metabolite factors, individuals with low blood folate ( < 11·5 nmol/l) or high mtDNA deletions (Δ threshold cycle number (Ct)>5·3) had increased risks for HCC (OR 7·7, 95 % CI 1·9, 29·9, P = 0·003; OR 5·4; 95 % CI 1·7, 16·8, P = 0·003, respectively). When combined with folate deficiency (serum folate < 14 nmol/l), the OR of HCC in individuals with high levels of lymphocytic mtDNA deletions was enhanced (OR 13·3; 95 % CI 1·45, 122; P = 0·008). Further controlling for GOT and GPT levels, however, negated those effects on HCC risk. Taken together, the data suggest that biochemical folate status and liver injuries are important modulators to lymphocytic mtDNA deletions. The mt genetic instability that results from a high rate of mtDNA deletions and/or low folate status increased the risk for HCC, which is mediated by clinical hepatic lesions.

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Corresponding author
*Corresponding author: Professor Rwei-Fen Syu Huang, fax +886 2 29021215, email 034825@mail.fju.edu.tw
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1 G Amuthan , G Biswas , SY Zhang , (2001) Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J 20, 19101920.

2 PF Chinnery , DC Samuels , J Elson , (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 13231325.

5 GA Cortopassi , DD Shibata , NW Soong , (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A 89, 73707374.

6 CT Moraes , S DiMauro , M Zeviani , (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med 320, 12931299.

7 MS Fliss , H Usadel , OL Caballero , (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287, 20172019.

10 C Jeronimo , S Nomoto , OL Caballero , (2001) Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20, 51955198.

12 M Fenech (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475, 5167.

15 SJ Duthie , G Grant & S Narayanan (2001) Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br J Cancer 83, 15321537.

18 RF Branda , EM Brooks , Z Chen , (2002) Dietary modulation of mitochondrial DNA deletions and copy number after chemotherapy in rats. Mutat Res 501, 2936.

19 JW Crott , SW Choi , RF Branda , (2005) Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res 570, 6370.

21 L Ravagnan , T Roumier & G Kroemer (2002) Mitochondria, the killer organelles and their weapons. J Cell Physiol 192, 131137.

22 DM Parkin , F Bray , J Ferlay , (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94, 153156.

23 YB Mikol , KL Hoover , D Creasia , (1983) Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 4, 16191629.

25 IP Pogribny , SJ James , S Jernigan , (2004) Genomic hypomethylation is specific for preneoplastic liver in folate/methyl deficient rats and does not occur in non-target tissues. Mutat Res 548, 5359.

26 TM Welzel , HA Katki & C Lori (2007) Blood folate levels and risk of liver damage and hepatocellular carcinoma in a prospective high-risk cohort. Cancer Epidemiol Biomarkers Prev 16, 12791282.

29 L He , RF Chinnery , SE Durham , (2002) Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acid Res 30, 6874.

32 H Yamamoto , M Tanaka , M Katayama , (1992) Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem Biophys Res Commun 182, 913920.

33 JY Shao , HY Gao , YH Li , (2004) Quantitative detection of common deletion of mitochondrial DNA in hepatocellular carcinoma and hepatocellular nodular hyperplasia. World J Gastroenterol 10, 15601564.

34 AM Lezza , D Boffoli , S Scacco , (1994) Correlation between mitochondrial DNA 4977-bp deletion and respiratory chain enzyme activities in aging human skeletal muscles. Biochem Biophys Res Commun 205, 772779.

36 KB Schwarz (1996) Oxidative stress during viral infection: a review. Free Radic Biol Med 21, 641649.

37 BM Rezk , GR Haenen , WJ van der Vijgh , (2003) Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore. FEBS Lett 555, 601605.

38 SN Doshi , IF McDowell , SJ Moat , (2001) Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21, 11961202.

42 K Tarao , Y Rino , S Ohkawa , (1999) Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer (Phila) 86, 589595.

44 ER Eichner & RS Hillman (1971) The evolution of anemia in alcoholic patients. Am J Med 50, 218232.

45 K Kotake , T Nonami , T Kurokawa , (1999) Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver. Life Sci 65, 557563.

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British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
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