臺灣博碩士論文加值系統

肝癌 (Hepatocellular carcinoma, HCC) 位居臺灣癌症死亡率的第一位，而許多證據顯示在肝癌的癌化過程中性荷爾蒙可能扮演某種角色。本論文發現三種雌激素代謝相關酵素的基因多型性，具有CYP17基因表現可能較高的A2對偶基因，較易被引發CYP1A1基因表現的MspI對偶基因，和產物酵素表現出較低活性的COMT基因L對偶基因會增加臺灣婦女罹患肝癌之危險性，而這三種多型性，與台灣地區男性罹患肝癌的危險性，並無統計上顯著的關聯。具有易被引發表現的MspI對偶基因的異合子個體其罹患肝癌之危險率（以及95% 信賴區間）為6.61（1.35, 32.43）， 而具有MspI對偶基因同合子之個體其罹患肝癌之危險率為12.00（1.73, 83.46）。此外具有愈多危險基因型，罹患肝癌的機率愈高，具有兩種危險基因型之個體，其罹患肝癌的危險率為12.63（1.50, 106.37），而具有三種危險基因型之個體，其罹患肝癌的危險率為16.67（1.82, 152.77），這個結果顯示雌激素的代謝在女性肝癌形成過程中扮演重要的角色。本論文並發現肝癌組織中粒線體內DNA及呼吸鏈蛋白質的含量較其相對應非癌肝臟組織低，此外有22%的肝癌病患其粒線體DNA的 D-loop的位置發生了突變。進一步的探討調控粒線體生合成基因的表現發現，肝癌組織中peroxisome proliferators-activated receptor □ coactivator-1的表現量明顯的降低，但mitochondrial single-strand DNA binding protein的表現量卻是增加的。此外和沒有長期飲酒史的肝癌病人相比，有長期飲酒史的肝癌病人其非癌肝組織內粒線體DNA的數目明顯減少，相反地粒線體DNA中4977鹼基對刪除突變所佔的比例卻明顯增加。使用低濃度EtBr處理HA22T/VGH肝癌細胞株可降低細胞內粒線體DNA的數目，而粒線體DNA數目較低的細胞其ATP含量較少並且生長速率較緩慢，對肝臟內雌性激素的主要代謝物二甲氧雌二醇及紫杉醇、doxorubicin等抗癌藥物的感受性提高，粒線體DNA數目較低的HA22T/VGH肝癌細胞株經二甲氧雌二醇處理後含四套以上染色體的細胞所增加的比例較少，細胞內的活性氧分子也並不會增加，這些可能是因為粒線體DNA數目較低的細胞內抗氧化蛋白基因的表現量增加所導致的結果，而粒線體DNA數目較低的細胞內Bcl家族蛋白的表現量增加可能導致其對抗癌藥物的感受性提高，這些結果顯示雌激素代謝的差異會影響肝癌的形成過程，而粒線體生合成機制的缺失以及粒線體DNA的突變在肝癌形成過程中扮演重要角色，此外粒線體數目的變異會影響細胞對雌激素代謝物及其他藥物的感受性，因此雌激素代謝差異與粒線體DNA數目變異的交互作用可能影響肝癌的形成、臨床表現以及對抗癌藥物的感受性。

Hepatocellular carcinoma (HCC) is the leading cause of cancer death in Taiwan, and many studies suggest that sex hormone plays a critical role in the carcinogenesis of this cancer. In this thesis, it was found that the estrogen-metabolizing gene polymorphisms (CYP17 A2, CYP1A1 MspI, or COMT L) raised the risk of HCC in women but not in men. The risk of HCC was elevated in women harboring either heterozygous or homozygous variants of the CYP1A1 gene and the respective odds ratio (and 95% confidence interval) were 6.61 (1.35, 32.43) and 12.00 (1.73, 83.46). Moreover, it was found that the risk of HCC was increased in the female subjects harboring higher numbers of high-risk genotypes, but not in male subjects. The OR for female HCC associated with two putative high-risk genotypes was 12.63 (1.50, 106.37), and the OR for three putative high-risk genotypes was 16.67 (1.82, 152.77). These findings strongly suggest that estrogen metabolism plays a critical role in female hepatocarcinogenesis. In addition, it was observed that mitochondrial DNA (mtDNA) copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with corresponding non-tumorous livers. Moreover, 22% of HCCs carried a somatic mutation in the mtDNA D-loop region. Expression of the peroxisome proliferator-activated receptor □ coactivator-1 was significantly repressed in HCCs (P<0.005) while the expression of the mitochondrial single strand DNA binding protein was up-regulated indicating the regulation of mitochondria biogenesis is disturbed in HCC. The non-tumorous liver of the HCC patients with a long-term alcohol drinking history contained reduced mtDNA copy number (P<0.05) and higher level of the 4,977 bp-deleted mtDNA (P<0.05) as compared with non-alcohol patients. These observations suggest that reduced mtDNA copy number, impaired mitochondrial biogenesis and somatic mutations in mtDNA are important events during carcinogenesis of HCC. In addition, a cell model of hepatoma cells harboring reduced mtDNA copy number was established by treating a hepatoma cell line HA22T/VGH with low concentration of ethidium bromide. It was found that the hepatoma cells harboring reduced mtDNA copy number have lower ATP content, slower proliferation rate, and higher susceptibility to 2-methoxyestradiol (2-ME), taxol as well as doxorubicin, respectively. Moreover, it was found that the proportion of the polyploidy cells induced by 2-ME was decreased in the hepatoma cells harboring reduced mtDNA content, and the intracellular level of reactive oxygen species was not elevated by 2-ME treatment. These alterations may result from increased antioxidant gene expression in the hepatoma cells harboring reduced mtDNA level. On the other hand, increased expression of the Bcl-2 family proteins in the hepatoma cells harboring reduced mtDNA copy number may lead to an increase in the susceptivity to anticancer drugs. These findings suggest that the decrease in mtDNA copy number of hepatoma cells elevate the susceptibility to 2-ME and anticancer drugs. In summary, interaction between the alteration in estrogen metabolism and the decrease in mtDNA copy number affect the carcinogenesis, clinical manifestation, and drug susceptivity of HCC.

參考文獻
1. Vital Statistic. Taipei, Taiwan, ROC: Department of Health, Executive Yuan, Health statistics of the Republic of China, 2004.
2. Nissen, N. N. and Matin, P. Hepatocellular carcinoma: the high-risk patient. J Clin Gastroenterol, 35: S79-85, 2002.
3. Murakami, S. Hepatitis B virus X protein: a multi-functional viral regulator. J Gastroenterol, 36: 651-660, 2001.
4. Chang, M. H., Chen, C. J., Lai, M. S., Hsu, H. M., Wu, T. C., Kong, M. S., Liang, D. C., Shau, W. Y., and Chen, D. S. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med, 336: 1855-1859, 1997.
5. Chan, C. Y., Lee, S. D., and Lo, K. J. Legend of hepatitis B vaccination: the Taiwan experience. J Gastroenterol Hepatol, 19: 121-126, 2004.
6. Monto, A. and Wright, T. L. The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol, 28: 441-449, 2001.
7. Tang, Z. Y. Hepatocellular carcinoma--cause, treatment and metastasis. World J Gastroenterol, 7: 445-454, 2001.
8. Nagasue, N., Galizia, G., Yukaya, H., Kohno, H., Chang, Y. C., Hayashi, T., and Nakamura, T. Better survival in women than in men after radical resection of hepatocellular carcinoma. Hepatogastroenterology, 36: 379-383, 1989.
9. El-Serag, H. B., Mason, A. C., and Key, C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology, 33: 62-65, 2001.
10. Jwo, S. C., Chiu, J. H., Chau, G. Y., Loong, C. C., and Lui, W. Y. Risk factors linked to tumor recurrence of human hepatocellular carcinoma after hepatic resection. Hepatology, 16: 1367-1371, 1992.
11. Kim, C. M., Koike, K., Saito, I., Miyamura, T., and Jay, G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature, 351: 317-320, 1991.
12. Moriya, K., Fujie, H., Shintani, Y., Yotsuyanagi, H., Tsutsumi, T., Ishibashi, K., Matsuura, Y., Kimura, S., Miyamura, T., and Koike, K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med, 4: 1065-1067, 1998.
13. De Maria, N., Manno, M., and Villa, E. Sex hormones and liver cancer. Mol Cell Endocrinol, 193: 59-63, 2002.
14. Kemp, C. J., Leary, C. N., and Drinkwater, N. R. Promotion of murine hepatocarcinogenesis by testosterone is androgen receptor-dependent but not cell autonomous. Proc Natl Acad Sci USA, 86: 7505-7509, 1989.
15. Toh, Y. C. Effect of neonatal castration on liver tumor induction by N-2-fluorenylacetamide in suckling BALB/c mice. Carcinogenesis, 2: 1219-1221, 1981.
16. Matsuura, B., Taniguki, Y., and Ohta, Y. Effect of antiandrogen treatment on chemical hepatocarcinogenesis in rats. J Hepatol, 21: 187-193, 1994.
17. Yu, M. W. and Chen, C. J. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res, 53: 790-794, 1993.
18. Nagasue, N., Ito, A., Yukaya, H., and Ogawa, Y. Androgen receptors in hepatocellular carcinoma and surrounding parenchyma. Gastroenterology, 89: 643-647, 1985.
19. Nagasue, N., Kohno, H., Chang, Y. C., Hayashi, T., Utsumi, Y., Nakamura, T., and Yukaya, H. Androgen and estrogen receptors in hepatocellular carcinoma and the surrounding liver in women. Cancer, 63: 112-116, 1989.
20. Ostrowski, J. L., Ingleton, P. M., Underwood, J. C., and Parsons, M. A. Increased hepatic androgen receptor expression in female rats during diethylnitrosamine liver carcinogenesis. A possible correlation with liver tumor development. Gastroenterology, 94: 1193-1200, 1988.
21. Eagon, P. K., Elm, M. S., Epley, M. J., Shinozuka, H., and Rao, K. N. Sex steroid metabolism and receptor status in hepatic hyperplasia and cancer in rats. Gastroenterology, 110: 1199-1207, 1996.
22. Nagasue, N., Yu, L., Yukaya, H., Kohno, H., and Nakamura, T. Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: impact on intrahepatic recurrence after hepatic resection. Br J Surg, 82: 542-547, 1995.
23. Yager, J. D., Zurlo, J., and Ni, N. Sex hormones and tumor promotion in liver. Proc Soc Exp Biol Med, 198: 667-674, 1991.
24. Coe, J. E., Ishak, K. I., and Ross, M. J. Estrogen induction of hepatocellular carcinoma in Armenian Hamsters. Hepatology, 11: 570-577, 1990.
25. Palmer, J. R., Rosenberg, L., Kaufman, D. W., Warshauer, M. E., Stolley, P., and Shapiro, S. Oral contraceptive use and liver cancer. Am J Epidemiol, 130: 878-882, 1989.
26. Kitamura, T., Watanabe, S., and Sato, N. Liver regeneration, liver cancers and cyclins. J Gastroenterol Hepatol, 13S: s96-99, 1998.
27. Francavilla, A., Polimeno, L., Barone, M., Azzarone, A., and Starzl, T. E. Hepatic regeneration and growth factors. J Surg Oncol Suppl, 3: 1-7, 1993.
28. Francavilla, A., Polimeno, L., Di Leo, A., Barone, M., Ove, P., Coetzee, M., Eagon, P., Makowka, L., Ambrosino, G., Mazzaferro, V., and Van Thiel, D. H. The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro. Hepatology, 9: 614-620, 1989.
29. Montalto, G., Miceli, M. D., Soresi, M., Amodio, R., Carroccio, A., Cartabellotta, A., and Castagnetta, L. Sex hormones in patients with liver cirrhosis and hepatocellular carcinoma. Oncol Rep, 4: 173-176, 1997.
30. Boix, L., Bruix, J., Castells, A., Fuster, J., Bru, C., Visa, J., Rivera, F., and Rodes, J. Sex hormone receptors in hepatocellular carcinoma. J Hepatol, 17, 1993.
31. Chao, Y., Chan, W. K., Huang, Y. S., Teng, H. C., Wang, S. S., Lui, W. Y., Whang-Peng, J., and Lee, S. D. Phase II study of flutamide in the treatment of hepatocellular carcinoma. Cancer, 77: 635-639, 1996.
32. Grimaldi, C., Bleiberg, H., Gay, F., Messner, M., Rougier, P., Kok, T. C., Cirera, L., Cervantes, A., De Greve, J., Paillot, B., Buset, M., Nitti, D., Sahmoud, T., Duez, N., and Wils, J. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol, 16: 411-417, 1998.
33. Liu, C. L., Fan, S. T., Ng, I. O., Lo, C. M., Poon, R. T., and Wong, J. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol, 95: 218-222, 2000.
34. Chao, Y., Chan, W. K., Wang, S. S., Lai, K. H., Chi, C. W., Lin, C. Y., Chan, A., Whang-Peng, J., Lui, W. Y., and Lee, S. D. Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma. J Gastroenterol Hepatol, 12: 277-281, 1997.
35. Pignarta, S., Daniele, B., Gallo, C., De Vivo, R., Monfardini, S., and Perrone, F. Endocrine treatment of hepatocellular carcinoma. Any Evidence of Benefit? Eur J Cancer, 34: 25-32, 1998.
36. Berg, D., Sonsalla, R., and Kuss, E. Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand. Acta Endocrinol (Copenh), 103: 282-288, 1983.
37. Seegers, J. C., Aveling, M. L., Van Aswegen, C. H., Cross, M., Koch, F., and Joubert, W. S. The cytotoxic effects of estradiol-17 beta, catecholestradiols and methoxyestradiols on dividing MCF-7 and HeLa cells. J Steroid Biochem, 32: 797-809, 1989.
38. LaVallee, T. M., Zhan, X. H., Herbstritt, C. J., Kough, E. C., Green, S. J., and Pribluda, V. S. 2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta. Cancer Res, 62: 3691-3697, 2002.
39. Zoubine, M. N., Weston, A. P., Johnson, D. C., Campbell, D. R., and Banerjee, S. K. 2-Methoxyestradiol-induced growth suppression and lethality in estrogen-responsive MCF-7 cells may be mediated by down regulation of p34cdc2 and cyclin B1 expression. Int J Oncol, 15: 639-646, 1999.
40. Lin, H. L., Liu, T. Y., Chau, G. Y., Lui, W. Y., and Chi, C. W. Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species. Cancer, 89: 983-994, 2000.
41. Lin, H. L., Liu, T. Y., Wu, C. W., and Chi, C. W. 2-Methoxyestradiol-induced caspase-3 activation and apoptosis occurs through G(2)/M arrest dependent and independent pathways in gastric carcinoma cells. Cancer, 92: 500-509, 2001.
42. Qanungo, S., Basu, A., Das, M., and Haldar, S. 2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells. Oncogene, 21: 4149-4157, 2002.
43. Kumar, A. P., Garcia, G. E., and Slaga, T. J. 2-Methoxyestradiol blocks cell-cycle progression at G2/M phase and inhibits growth of human prostate cancer cells. Mol Carcinog, 31: 111-124, 2001.
44. Fotsis, T., Zhang, Y., Pepper, M. S., Adlercreutz, H., Montesano, R., Nawroth, P. P., and Schweigerer, L. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature, 368: 237-239, 1994.
45. Seegers, J. C., Lottering, M. L., Grobler, C. J., van Papendorp, D. H., Habbersett, R. C., Shou, Y., and Lehnert, B. E. The mammalian metabolite, 2-methoxyestradiol, affects P53 levels and apoptosis induction in transformed cells but not in normal cells. J Steroid Biochem Mol Biol, 62: 253-267, 1997.
46. Pribluda, V. S., Gubish, E. R., Jr., Lavallee, T. M., Treston, A., Swartz, G. M., and Green, S. J. 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate. Cancer Metastasis Rev, 19: 173-179, 2000.
47. Mukhopadhyay, T. and Roth, J. A. Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene, 14: 379-384, 1997.
48. Huober, J. B., Nakamura, S., Meyn, R., Roth, J. A., and Mukhopadhyay, T. Oral administration of an estrogen metabolite-induced potentiation of radiation antitumor effects in presence of wild-type p53 in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys, 48: 1127-1137, 2000.
49. Attalla, H., Westberg, J. A., Andersson, L. C., Adlercreutz, H., and Makela, T. P. 2-Methoxyestradiol-induced phosphorylation of Bcl-2: uncoupling from JNK/SAPK activation. Biochem Biophys Res Commun, 247: 616-619, 1998.
50. Lui, W. Y., P''Eng F, K., Liu, T. Y., and Chi, C. W. Hormonal therapy for hepatocellular carcinoma. Med Hypotheses, 36: 162-165, 1991.
51. IARC. IARC Monographs on the Evaluation of Carcinogen Risk of Chemicals to Man. Overall Evaluations of Carcinogenicity: an updating of IARC monographs Vol 1 to 42. In, Vol. Supplement 7. France: IARC Lyon, 1987.
52. Liehr, J. G. Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev, 21: 40-54, 2000.
53. Hiraku, Y., Yamashita, N., Nishiguchi, M., and Kawanishi, S. Catechol estrogens induce oxidative DNA damage and estadiol enhances cell proliferation. Int J Cancer, 92: 333-337, 2001.
54. Preston-Martin, S., Pike, M. C., Ross, R. K., Jones, P. A., and Henderson, B. E. Increased cell division as a cause of human cancer. Cancer Res, 50: 7415-7421, 1990.
55. Yue, W., Santen a, R. J., Wang, J. P., Lia, Y., Verderame, M. F., Bocchinfuso, W. P., Korach, K. S., Devanesan, P., Todorovic, R., Rogand, E. G., and Cavalieri, E. L. Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol, 86: 477-486, 2003.
56. Cavalieri, E., Frenkel, K., Liehr, J. G., Rogan, E., and Roy, D. Estrogens as endogenous genotoxic agents-DNA adducts and mutations. J Natl Cancer Inst Monogr, 27: 75-93, 2000.
57. Martucci, C. P. and Fishman, J. P450 enzymes of estrogen metabolism. Pharmacol Ther, 57: 237-257, 1993.
58. Zhu, B. T. and Conney, A. H. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis, 19: 1-27, 1998.
59. Nutter, L. M., Wu, Y. Y., Ngo, E. O., Sierra, E. E., Gutierrez, P. L., and Abul-Hajj, Y. J. An o-quinone form of estrogen produces free radicals in human breast cancer cells: correlation with DNA damage. Chem Res Toxicol, 7: 23-28, 1994.
60. Tabakovic, K., Gleason, W. B., Ojala, W. H., and Abul-Hajj, Y. J. Oxidative transformation of 2-hydroxyestrone. Stability and reactivity of 2,3-estrone quinone and its relationship to estrogen carcinogenicity. Chem Res Toxicol, 9: 860-865, 1996.
61. Lloyd, R. V., Hanna, P. M., and Mason, R. P. The origin of the hydroxyl radical oxygen in the Fenton reaction. Free Radic Biol Med, 22: 885-888, 1997.
62. Tan, X., Grollman, A. P., and Shibutani, S. Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2''-deoxyadenosine and 8-oxo-7,8-dihydro-2''-deoxyguanosine DNA lesions in mammalian cells. Carcinogenesis, 20: 2287-2292, 1999.
63. Stack, D. E., Byun, J., Gross, M. L., Rogan, E. G., and Cavalieri, E. L. Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides. Chem Res Toxicol, 9: 851-859, 1996.
64. Shibutani, S., Takeshita, M., and Grollman, A. P. Translational synthesis on DNA templates containing a single abasic site. A mechanistic study of the "A rule". J Biol Chem, 272: 13916-13922, 1997.
65. Terashima, I., Suzuki, N., and Shibutani, S. Mutagenic properties of estrogen quinone-derived DNA adducts in simian kidney cells. Biochemistry (Mosc), 40: 166-172, 2001.
66. Huber, J. C., Schneeberger, C., and Tempfer, C. B. Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders. Maturitas, 42: 1-12, 2002.
67. Kristensen, V. N. and Borresen-Dale, A. L. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Mutat Res, 462: 323-333, 2000.
68. Picado-Leonard, J. and Miller, W. L. Cloning and sequence of the human gene for P450c17 [steroid 17a-hydroxylase/17,20 lyase]: similarity with the gene for P450c21. DNA, 6: 439-448, 1987.
69. Carey, A. H., Waterworth, D., Patel, K., White, D., Little, J., Novelli, P., Franks, S., and Williamson, R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet, 3: 1873-1876, 1994.
70. Feigelson, H. S., Shames, L. S., Pike, M. C., Coetzee, G. A., Stanczyk, F. Z., and Henderson, B. E. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res, 58: 585-587, 1998.
71. Feigelson, H. S., Coetzee, G. A., Kolonel, L. N., Ross, R. K., and Henderson, B. E. A polymorphism in the CYP17 gene increases the risk of breast cancer. Cancer Res, 57: 1063-1065, 1997.
72. Bergman-Jungestrom, M., Gentile, M., Lundin, A. C., and Wingren, S. Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer, 84: 350-353, 1999.
73. Young, I. E., Kurian, K. M., Annink, C., Kunkler, I. H., Anderson, V. A., Cohen, B. B., Hooper, M. L., Wyllie, A. H., and Steel, C. M. A polymorphism in the CYP17 gene is associated with male breast cancer. Br J Cancer, 81: 141-143, 1999.
74. Huang, C. S., Shen, C. Y., Chang, K. J., Hsu, S. M., and Chern, H. D. Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Br J Cancer, 80: 1838-1843, 1999.
75. Taioli, E., Trachman, J., Chen, X., Toniolo, P., and Garte, S. J. A CYP1A1 restriction fragment length polymorphism is associated with breast cancer in African-American women. Cancer Res, 55: 3757-3758, 1995.
76. Ambrosone, C. B., Freudenheim, J. L., Graham, S., Marshall, J. R., Vena, J. E., Brasure, J. R., Laughlin, R., Nemoto, T., Michalek, A. M., Harrington, A., Ford, T. D., and Shields, P. G. Cytochrome P4501A1 and glutathione-S-transferase (M1) genetic polymorphism and postmenopausal breast cancer risk. Cancer Res, 55: 3483-3485, 1995.
77. Yager, J. D. and G., L. J. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol, 36: 203-232, 1996.
78. Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y. M., Szumlanski, C. L., and Weinshilboum, R. M. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics, 6: 243-250, 1996.
79. Dawling, S., Roodi, N., Mernaugh, R. L., Wang, X., and Parl, F. F. Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer Res, 61: 6716-6722, 2001.
80. Huang, C. S., Chern, H. D., Chang, K. J., Cheng, C. W., Hsu, S. M., and Shen, C. Y. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res, 59: 4870-4875, 1999.
81. Weisz, J., Clawson, G. A., and Creveling, C. R. Biogenesis and inactivation of catecholestrogens. Adv Pharmacol, 42: 823-833, 1998.
82. Lee, H. C. and Wei, Y. H. Mitochondrial role in life and death of the cell. J Biomed Sci, 7: 2-15, 2000.
83. Boveris, A. and Chance, B. The mitochondrial generation of hydrogen peroxide: general properties and effect of hyperbaric oxygen. Biochem J, 134: 707-716, 1973.
84. Taanman, J. W. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta, 1410: 103-123, 1999.
85. Anderson, S., Bankier, A. T., Barrell, B. G., deBruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., and Young, I. G. Sequence and organization of the human mitochondrial genome. Nature, 290: 457-465, 1981.
86. Attardi, G. and Schatz, G. Biogenesis of mitochondria. Annu Rev Cell Biol, 4: 289-333, 1988.
87. Poyton, R. O. and McEwen, J. E. Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem, 65: 563-607., 1996.
88. Shadel, G. S. and Clayton, D. A. Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem, 66: 409-435, 1997.
89. Shadel, G. S. and Clayton, D. A. Mitochondrial transcription initiation. Variation and conservation. J Biol Chem, 268: 16083-16086, 1993.
90. Xu, B. and Clayton, D. A. RNA-DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites: an implication for RNA-DNA hybrids serving as primers. EMBO J, 15: 3135-3143, 1996.
91. Dairaghi, D. J., Shadel, G. S., and Clayton, D. A. Human mitochondrial transcription factor A and promoter spacing integrity are required for transcription initiation. Biochim Biophys Acta, 1271: 127-134, 1995.
92. Moraes, C. T. What regulates mitochondrial DNA copy in animal cells? Trends in Genet, 17: 199-205, 2001.
93. Schultz, R. A., Swoap, S. J., McDaniel, L. D., Zhang, B., Koon, E. C., Garry, D. J., and Li, K. Differential expression of mitochondrial DNA replication factors in mammalian tissues. J Biol Chem, 273: 3447-3451, 1998.
94. Virbasius, J. V. and Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A, 91: 1309-1313, 1994.
95. Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., and Clayton, D. A. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet, 18: 231-236, 1998.
96. Scarpulla, R. C. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene, 286: 81-89, 2002.
97. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., and Spiegelman, B. M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell, 98: 115-124, 1999.
98. Richter, C., Gogvadze, V., Laffranchi, R., Schlapbach, R., Schnizer, M., Suter, M., Walter, P., and Yaffee, M. Oxidants in mitochondria: from physiology to disease. Biochim Biophys Acta, 1271: 67-74, 1995.
99. Sawyer, D. E. and Van Houten, B. Repair of DNA damage in mitochondria. Mutat Res, 434: 161-176, 1999.
100. Yakes, F. M. and van Houten, B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA, 94: 514-519, 1997.
101. Croteau, D. L. and Bohr, V. A. Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem, 272: 25409-25412, 1997.
102. Garcia-Ruiz, C., Colell, A., Morales, A., Kaplowitz, N., and Fernandez-Checa, J. C. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kB: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol, 48: 825-834, 1995.
103. Wallace, D. C. Mitochondrial diseases in man and mouse. Science, 283: 1482-1488, 1999.
104. Lee, H. C. and Wei, Y. H. Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging. J Formos Med Assoc, 96: 770-778, 1997.
105. Lee, H. C. and Wei, Y. H. The role of mitochondria in human aging. J Biomed Sci, 4: 319-326, 1997.
106. Wei, Y. H. Mitochondrial DNA alterations as aging-associated molecular events. Mutat Res, 275: 145-155, 1992.
107. Wei, Y. H. Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med, 217: 53-63, 1998.
108. Lee, H. C., Lim, M. L. R., Lu, C. Y., Liu, V. W. S., Fahn, H. J., Zhang, C., Nagley, P., and Wei, Y. H. Concurrent increase of oxidative DNA damage and lipid peroxidation together with mitochondrial DNA mutation in human lung tissues during aging-smoking enhances oxidative stress on the aged tissues. Arch Biochem Biophys, 362: 309-316, 1999.
109. Yen, T. C., King, K. L., Lee, H. C., Yeh, S. H., and Wei, Y. H. Age-dependent increase of mitochondrial DNA deletions together with lipid peroxides and superoxide dismutase in human liver mitochondria. Free Radic Biol Med, 16: 207-214, 1994.
110. Wei, Y. H., Kao, S. H., and Lee, H. C. Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging. Ann N Y Acad Sci, 786: 24-43, 1996.
111. Barrientos, A., Casademont, J., Cardellach, F., Ardite, E., Estivill, X., Urbano-Marquez, A., Fernandez-Checa, J. C., and Nunes, V. Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process. Biochem Mol Med, 62: 165-171, 1997.
112. Barrientos, A., Casademont, J., Cardellach, F., Estivill, X., Urbano-Marquez, A., and Nunes, V. Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging. Mol Brain Res, 52: 284-289, 1997.
113. Lee, H. C., Lu, C. Y., Fahn, H. J., and Wei, Y. H. Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. FEBS Lett, 441: 292-296, 1998.
114. Ames, B. N., Shigenaga, M. K., and Hagen, T. M. Mitochondrial decay in aging. Biochim Biophys Acta, 1271: 165-170, 1995.
115. Lee, H. C., Yin, P. H., Lu, C. Y., Chi, C. W., and Wei, Y. H. Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J, 348: 425-432, 2000.
116. Lee, H. C., Yin, P. H., Chi, C. W., and Wei, Y. H. Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence. J Biomed Sci, 9: 517-526, 2002.
117. Thompson, C. B. Apoptosis in the pathogenesis and treatment of disease. Science, 267: 1456-1462, 1995.
118. Kluck, R. M., Bossy-Wetzel, E., Green, D. R., and Newmeyer, D. D. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science, 275: 1132-1136, 1997.
119. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade. Cell, 91: 479-489, 1997.
120. Budihardjo, I., Oliver, H., Lutter, M., Luo, X., and Wang, X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol, 15: 269-290, 1999.
121. Skulachev, V. P. Cytochrome c in the apoptotic and antioxidant cascades. FEBS Lett, 423: 275-280, 1998.
122. Kroemer, G. and Reed, J. C. Mitochondrial control of cell death. Nature Med, 6: 513-519, 2000.
123. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., and Kroemer, G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature, 397: 441-446, 1999.
124. Luo, X., Budihardjo, I., Zou, H., Slaughter, C., and Wang, X. D. Bid, a Bcl-2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell, 94: 481-490, 1998.
125. Adams, J. M. and Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science, 281: 1322-1326, 1998.
126. Krajewski, S., Tanaka, S., Takayama, S., Schibler, M. J., Fenton, W., and Reed, J. C. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res, 53: 4701-4714, 1993.
127. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, II, Jones, D. P., and Wang, X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science, 275: 1129-1132, 1997.
128. Kane, D. J., Sarafian, T. A., Anton, R., Hahn, H., Gralla, E. B., Valentine, J. C., Ord, T., and Bredesen, D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science, 262: 1274-1277, 1993.
129. van der Heiden, M. G., Chandel, N. S., Schumacker, P. T., and Thompson, C. B. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell, 3: 159-167, 1999.
130. Schlesinger, P. H., Gross, A., Yin, X. M., Yamamoto, K., Saito, M., Waksman, G., and Korsmeyer, S. J. Comparison of the ion channel characteristics of proapoptotic Bax and antiapoptotic Bcl-2. Proc Natl Acad Sci USA, 94: 11357-11362, 1997.
131. Hu, Y., Benedict, M. A., Wu, D., Inohara, N., and Nunez, G. Bcl-xL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA, 95: 4386-4391, 1998.
132. Marchenko, N. D., Zaika, A., and Moll, U. M. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem, 275: 16202-16212, 2000.
133. Kharbanda, S., Saxena, S., Yoshida, K., Pandey, P., Kaneki, M., Wang, Q., Cheng, K., Chen, Y. N., Campbell, A., Sudha, T., Yuan, Z. M., Narula, J., Weichselbaum, R., Nalin, C., and Kufe, D. Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. J Biol Chem, 275: 322-327, 2000.
134. Brown, G. C. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem J, 284: 1-13, 1992.
135. Shay, J. W. and Werbin, H. Are mitochondrial DNA mutations involved in the carcinogenic process. Mutat Res, 186: 149-160, 1987.
136. Richter, C. Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett, 241: 1-5, 1988.
137. Bandy, B. and Davison, A. J. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging. Mutat Res, 8: 523-539, 1990.
138. Hochhauser, D. Relevance of mitochondrial DNA in cancer. Lancet, 356: 181-182, 2000.
139. Cavalli, L. R. and Liang, B. C. Mutagenesis, tumorigenicity, and apoptosis: are the mitochondria involved? Mutat Res, 398: 19-26, 1998.
140. Carew, J. S. and Huang, P. Mitochondrial defects in cancer. Mol Cancer, 1: 9, 2002.
141. Polyak, K., Li, Y., Zhu, H., Lengauer, C., Willson, J. K., Markowitz, S. D., Trush, M. A., Kinzler, K. W., and Vogelstein, B. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genet, 20: 291-293, 1998.
142. Fliss, M. S., Usadel, H., Caballero, O. L., Wu, L., Buta, M. R., Eleff, S. M., Jen, J., and Sidransky, D. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science, 287: 2017-2019, 2000.
143. Kotake, K., Nonami, T., Kurokawa, T., Nakao, A., Murakami, Y., and Shimomura, Y. Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers. Life Sci, 64: 1785-1791, 1999.
144. Tamura, G., Nishizuka, S., Maesawa, C., Suzuki, Y., Iwaya, T., Sakata, K., Endoh, Y., and Motoyama, T. Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients. Eur J Cancer, 35: 316-319, 1999.
145. Liu, V. W. S., Shi, H. H., Cheung, A. N. Y., Chiu, P. M., Leung, T. W., Nagley, P., Wong, L. C., and Ngan, H. Y. S. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res, 61: 5998-6001, 2001.
146. Richard, S. M., Bailliet, G., Paez, G. L., Bianchi, M. S., Peltomaki, P., and Bianchi, N. O. Nuclear and mitochondrial genome instability in human breast cancer. Cancer Res, 60: 4231-4237, 2000.
147. Pang, C. Y., Lee, H. C., Yang, J. H., and Wei, Y. H. Human skin mitochondrial DNA deletions associated with light exposure. Arch Biochem Biophys, 312: 534-538, 1994.
148. Durham, S. E., Krishnan, K. J., Betts, J., and Birch-Machin, M. A. Mitochondrial DNA damage in non-melanoma skin cancer. Br J Cancer, 88: 90-95, 2003.
149. Lee, H. C., Yin, P. H., Yu, T. N., Chang, Y. D., Hsu, W. C., Kao, S. Y., Chi, C. W., Liu, T. Y., and Wei, Y. H. Accumulation of mitochondrial DNA deletions in human oral tissues--Effects of betel quid chewing and oral cancer. Mutat Res, 493: 67-74, 2001.
150. Bianchi, N. O., Bianchi, M. S., and Richard, S. M. Mitochondrial genome instability in human cancers. Mutat Res, 488: 9-23, 2001.
151. Yager, J. D. Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monogr 67-73, 2000.
152. Chen, J., Gokhale, M., Li, Y., Trush, M. A., and Yager, J. D. Enhanced levels of several mitochondrial mRNA transcripts and mitochondrial superoxide production during ethinyl estradiol-induced hepatocarcinogenesis and after estrogen treatment of HepG2. Carcinogenesis, 19: 2187-2193, 1998.
153. Karbowski, M., Spodnik, J. H., Teranishi, M., Wozniak, M., Nishizawa, Y., Usukura, J., and Wakabayashi, T. Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J Cell Sci, 114: 281-291, 2001.
154. Nishikawa, M., Nishiguchi, S., Shiomi, S., Tamori, A., Koh, N., Takeda, T., Kubo, S., Hirohashi, K., Sato, E., and Inoue, M. Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma. Cancer Res, 61: 1843-1845, 2001.
155. Guerrieri, F., Muolo, L., Cocco, T., Capozza, G., Turturro, N., Cantatore, P., and Papa, S. Correlation between rat liver regeneration and mitochondrial energy metabolism. Biochim Biophys Acta, 1272: 95-100, 1995.
156. Nagino, M., Tanaka, M., Nishikimi, M., Nimura, Y., Kubota, H., Kanai, M., Kato, T., and Ozawa, T. Stimulated rat liver mitochondrial biogenesis after partial hepatectomy. Cancer Res, 49: 4913-4918, 1989.
157. Koyama, H., Kurokawa, T., Nonami, T., Nakao, A., Sugiyama, S., Murakami, T., and Shimomura, Y. Increases in the mitochondrial DNA replication and transcription in the remnant liver of rats. Biochem Biophys Res Commun, 243: 858-861, 1998.
158. Van den Bogert, C., Lont, M., Mojet, M., and Kroon, A. M. Impairment of liver regeneration during inhibition of mitochondrial protein synthesis by oxytetracycline. Biochim Biophys Acta, 722: 393-400, 1983.
159. Lee, H. C., Li, S. H., Lin, J. C., Wu, C. C., Yeh, D. C., and Wei, Y. H. Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma. Mutat Res, 547: 71-78, 2004.
160. Lee, H. C., Pang, C. Y., Hsu, H. S., and Wei, Y. H. Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta, 1226: 37-43, 1994.
161. Lee, H. C., Yin, P. H., Yu, T. N., Chang, Y. D., Hsu, W. C., Kao, S. Y., Chi, C. W., Liu, T. Y., and Wei, Y. H. Accumulation of mitochondrial DNA deletions in human oral tissues -- effects of betel quid chewing and oral cancer. Mutat Res, 493: 67-74, 2001.
162. Lin, Y. M., Hu, C. P., Chou, C. K., TW, O. L., Wuu, K. T., Chen, T. Y., Peng, F. K., Liu, T. J., Ko, J. L., and Chang, C. M. [A new human hepatoma cell line: establishment and characterization]. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi, 15: 193-201, 1982.
163. Lui, W. Y., Chang, Y. F., Li, L. L., Ho, L. K., Su, T. L., Chen, J. Y., Liu, T. Y., P''Eng, F. K., and Chi, C. W. Differential paclitaxel-induced cytotoxicity in rodent and human hepatoma cell lines. Anticancer Research., 18: 3339-3345, 1998.
164. Miyoshi, Y. and Noguchi, S. Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. Biomed Pharmacother, 57: 471-481, 2003.
165. Haiman, C. A., Hankinson, S. E., Spiegelman, D., Colditz, G. A., Willett, W. C., Speizer, F. E., Kelsey, K. T., and Hunter, D. J. The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res, 59: 1015-1020, 1999.
166. Garner, E. I., Stokes, E. E., Berkowitz, R. S., Mok, S. C., and Cramer, D. W. Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer. Cancer Res, 62: 3058-3062, 2002.
167. Gsur, A., Bernhofer, G., Hinteregger, S., Haidinger, G., Schatzl, G., Madersbacher, S., Marberger, M., Vutuc, C., and Micksche, M. A polymorphism in the CYP17 gene is associated with prostate cancer risk. Int J Cancer, 87: 434-437, 2000.
168. Kristensen, V. N., Haraldsen, E. K., Andersson, K. B., Lonning, P. E., Erikstein, B., Karesen, R., Gabrielsen, O. S., and Borresen-Dale, A. L. CYP17 and breast cancer risk: the polymorphism in the 5'' flanking area of the gene does not influence binding to Sp-1. Cancer Res, 59: 2825-2828, 1999.
169. Habuchi, T., Liqing, Z., Suzuki, T., Sasaki, R., Tsuchiya, N., Tachiki, H., Shimoda, N., Satoh, S., Sato, K., Kakehi, Y., Kamoto, T., Ogawa, O., and Kato, T. Increased risk of prostate cancer and benign prostatic hyperplasia associated with a CYP17 gene polymorphism with a gene dosage effect. Cancer Res, 60: 5710-5713, 2000.
170. Goodman, J. E., Lavigne, J. A., Hengstler, J. G., Tanner, B., Helzlsouer, K. J., and Yager, J. D. Catechol-O-methyltransferase polymorphism is not associated with ovarian cancer risk. Cancer Epidemiol Biomarkers Prev, 9: 1373-1376, 2000.
171. Walker, N. J., Portier, C. J., Lax, S. F., Crofts, F. G., Li, Y., Lucier, G. W., and Sutter, T. R. Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetracholrodibenzo-p-dioxin. Toxicol Appl Pharmacol, 154: 279-286, 1999.
172. Lucier, G. W., Tritscher, A., Goldsworthy, T., Foley, J., Clark, G., Goldstein, J., and Maronpot, R. Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis. Cancer Res, 51: 1391-1397, 1991.
173. Wyde, M. E., Eldridge, S. R., Lucier, G. W., and Walker, N. J. Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced tumor promotion by 17 beta-estradiol in female Sprague--Dawley rats. Toxicol Appl Pharmacol, 173: 7-17, 2001.
174. Wyde, M. E., Cambre, T., Lebetkin, M., Eldridge, S. R., and Walker, N. J. Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in male Sprague-Dawley rats. Toxicol Sci, 68: 295-303, 2002.
175. Tritscher, A. M., Seacat, A. M., Yager, J. D., Groopman, J. D., Miller, B. D., Bell, D., Sutter, T. R., and Lucier, G. W. Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Lett, 98: 219-225, 1996.
176. Wyde, M. E., Wong, V. A., Kim, A. H., Lucier, G. W., and Walker, N. J. Induction of hepatic 8-oxo-deoxyguanosine adducts by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sprague-Dawley rats is female-specific and estrogen-dependent. Chem Res Toxicol, 14: 849-855, 2001.
177. Tharappel, J. C., Lee, E. Y., Robertson, L. W., Spear, B. T., and Glauert, H. P. Regulation of cell proliferation, apoptosis, and transcription factor activities during the promotion of liver carcinogenesis by polychlorinated biphenyls. Toxicol Appl Pharmacol, 179: 172-184, 2002.
178. Mayes, B. A., McConnell, E. E., Neal, B. H., Brunner, M. J., Hamilton, S. B., Sullivan, T. M., Peters, A. C., Ryan, M. J., Toft, J. D., Singer, A. W., Brown, J. F., Jr., Menton, R. G., and Moore, J. A. Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260. Toxicol Sci, 41: 62-76, 1998.
179. Segura-Aguilar, J., Castro, V., and Bergman, A. Effects of four organohalogen environmental contaminants on cytochrome P450 forms that catalyze 4- and 2-hydroxylation of estradiol in the rat liver. Biochem Mol Med, 60: 149-154, 1997.
180. Garner, C. E., Burka, L. T., Etheridge, A. E., and Matthews, H. B. Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens. Toxicol Appl Pharmacol, 162: 115-123, 2000.
181. Tapiero, H., Ba, G. N., and Tew, K. D. Estrogens and environmental estrogens. Biomed Pharmacother, 56: 36-44, 2002.
182. Mucci, L. A., Kuper, H. E., Tamimi, R., Lagiou, P., Spanos, E., and Trichopoulos, D. Age at menarche and age at menopause in relation to hepatocellular carcinoma in women. Br J Obstet Gynaecol, 108: 291-294, 2001.
183. Yu, M. W., Chang, H. C., Chang, S. C., Liaw, Y. F., Lin, S. M., Liu, C. J., Lee, S. D., Lin, C. L., Chen, P. J., Lin, C. B., and Chen, C. J. Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology, 38: 1393-1400, 2003.
184. Augenlicht, L. H. and Heerdt, B. G. Mitochondria: integrators in tumorigenesis? Nat Genet, 28: 104-105, 2001.
185. Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., and Adelmant, G. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature, 413: 131-138, 2001.
186. Warburg, O. On the origin of cancer cells. Science, 123: 309-314, 1956.
187. Dang, C. V. and Semenza, G. L. Oncogenic alterations of metabolism. Trends Biochem Sci, 24: 68-72, 1999.
188. Meierhofer, D., Mayr, J. A., Foetschl, U., Berger, A., Fink, K., Schmeller, N., Hacker, G. W., Hauser-Kronberger, C., Kofler, B., and Sperl, W. Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma. Carcinogenesis, 25: 1005-1010, 2004.
189. Simonnet, H., Alazard, N., Pfeiffer, K., Gallou, C., Beroud, C., Demont, J., Bouvier, R., Schagger, H., and Godinot, C. Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. Carcinogenesis, 23: 759-768, 2002.
190. Cuezva, J. M., Krajewska, M., De Heredia, M. L., Krajewski, S., Santamaria, G., Kim, H., and Zapata, J. M. The bioenergenic signature of cancer: a marker of tumor progression. Cancer Res, 62: 6674-6681, 2002.
191. Capuano, F., Varone, D., D''Eri, N., Russo, E., Tommasi, S., Montemurro, S., Prete, F., and Papa, S. Oxidative phosphorylation and F(O)F(1) ATP synthase activity of human hepatocellular carcinoma. Biochem Mol Biol Int, 38: 1013-1022, 1996.
192. Scarpulla, R. C. Nuclear control of respiratory chain expression in mammalian cells. J Bioenerg Biomembr, 29: 109-119, 1997.
193. Pinz, K. G., Shibutani, S., and Bogenhagen, D. F. Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. J Biol Chem, 270: 9202-9206, 1995.
194. Copeland, W. C., Wachsman, J. T., Johnson, F. M., and Penta, J. S. Mitochondrial DNA alterations in cancer. Cancer Invest, 20: 557-569, 2002.
195. Penta, J. S., Johnson, F. M., Wachsman, J. T., and Copeland, W. C. Mitochondrial DNA in human malignancy. Mutat Res, 488: 119-133, 2001.
196. Ling, X. L., Fang, D. C., Wang, R. Q., Yang, S. M., and Fang, L. Mitochondrial microsatellite instability in gastric cancer and its precancerous lesions. World J Gastroenterol, 10: 800-803, 2004.
197. Fang, D. C., Fang, L., Wang, R. Q., and Yang, S. M. Nuclear and mitochondrial DNA microsatellite instability in hepatocellular carcinoma in Chinese. World J Gastroenterol, 10: 371-375, 2004.
198. Ha, P. K., Tong, B. C., Westra, W. H., Sanchez-Cespedes, M., Parrella, P., Zahurak, M., Sidransky, D., and Califano, J. A. Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation. Clin Cancer Res, 8: 2260-2265, 2002.
199. Sanchez-Cespedes, M., Parrella, P., Nomoto, S., Cohen, D., Xiao, Y., Esteller, M., Jeronimo, C., Jordan, R. C., Nicol, T., Koch, W. M., Schoenberg, M., Mazzarelli, P., Fazio, V. M., and Sidransky, D. Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res, 61: 7015-7019, 2001.
200. Okochi, O., Hibi, K., Uemura, T., Inoue, S., Takeda, S., Kaneko, T., and Nakao, A. Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients. Clin Cancer Res, 8: 2875-2878, 2002.
201. Mambo, E., Gao, X., Cohen, Y., Guo, Z., Talalay, P., and Sidransky, D. Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc Natl Acad Sci U S A, 100: 1838-1843, 2003.
202. Toyokuni, S., Okamoto, K., Yodoi, J., and Hiai, H. Persistent oxidative stress in cancer. FEBS Lett, 358: 1-3, 1995.
203. Chen, C. J., Yu, M. W., and Liaw, Y. F. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol, 12: S294-308, 1997.
204. Cederbaum, A. I. Effects of alcohol on hepatic mitochondrial function and DNA. Gastroenterology, 117: 265-269, 1999.
205. Demeilliers, C., Maisonneuve, C., Grodet, A., Mansouri, A., Nguyen, R., Tinel, M., Letteron, P., Degott, C., Feldmann, G., Pessayre, D., and Fromenty, B. Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice. Gastroenterology, 123: 1278-1290, 2002.
206. Mansouri, A., Fromenty, B., Berson, A., Robin, M. A., Grimbert, S., Beaugrand, M., Erlinger, S., and Pessayre, D. Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients. J Hepatol, 27: 96-102, 1997.
207. Borras, C., Sastre, J., Garcia-Sala, D., Lloret, A., Pallardo, F. V., and Vina, J. Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med, 34: 546-552, 2003.
208. Bhat, H. K. Depletion of mitochondrial DNA and enzyme in estrogen-induced hamster kidney tumors: a rodent model of hormonal carcinogenesis. J Biochem Mol Toxicol, 16: 1-9, 2002.
209. Huang, P., Feng, L., Oldham, E. A., Keating, M. J., and Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature, 407: 390-395, 2000.
210. Kachadourian, R., Liochev, S. I., Cabelli, D. E., Patel, M. N., Fridovich, I., and Day, B. J. 2-Methoxyestradiol does not inhibit superoxide dismutase. Arch Biochem Biophys, 392: 349-353, 2001.
211. Djavaheri-Mergny, M., Wietzerbin, J., and Besancon, F. 2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production. Oncogene, 22: 2558-2567, 2003.
212. King, M. P. and Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science, 246: 500-503, 1989.
213. Zylber, E., Vesco, C., and Penman, S. Selective inhibition of the synthesis of mitochondria-associated RNA by ethidium bromide. J Mol Biol, 44: 195-204, 1969.
214. Sen, S., Mukhopadhyay, S., Wetzel, J., and Biswas, T. K. Characterization of the mitochondrial DNA polymerase from Saccharomyces cerevisiae. Acta Biochim Pol, 41: 79-86, 1994.
215. Gilkerson, R. W., Margineantu, D. H., Capaldi, R. A., and Selker, J. M. Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells. FEBS Lett, 474: 1-4, 2000.
216. Tabouy, L., Zamora, A. J., Oliva, L., Montet, A. M., Beauge, F., and Montet, J. C. Ursodeoxycholate protects against ethanol-induced liver mitochondrial injury. Life Sci, 63: 2259-2270, 1998.
217. Wiggers, H., Noreng, M., Paulsen, P. K., Bottcher, M., Egeblad, H., Nielsen, T. T., and Botker, H. E. Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans. J Am Coll Cardiol, 37: 100-108, 2001.
218. Park, K. S., Nam, K. J., Kim, J. W., Lee, Y. B., Han, C. Y., Jeong, J. K., Lee, H. K., and Pak, Y. K. Depletion of mitochondrial DNA alters glucose metabolism in SK-Hep1 cells. Am J Physiol Endocrinol Metab, 280: E1007-1014, 2001.
219. Buchet, K. and Godinot, C. Functional F1-ATPase essential in maintaining growth and membrane potential of human mitochondrial DNA-depleted r0 cells. J Biol Chem, 273: 22983-22989, 1998.
220. Tian, W. N., Braunstein, L. D., Pang, J., Stuhlmeier, K. M., Xi, Q. C., Tian, X., and Stanton, R. C. Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J Biol Chem, 273: 10609-10617, 1998.
221. Singh, K. K., Russell, J., Sigala, B., Zhang, Y., Williams, J., and Keshav, K. F. Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene, 18: 6641-6646, 1999.
222. Zhou, S., Palmeira, C. M., and Wallace, K. B. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett, 121: 151-157, 2001.
223. Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I., and Gottesman, M. M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol, 39: 361-398, 1999.
224. Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E., and Gottesman, M. M. P-glycoprotein: from genomics to mechanism. Oncogene, 22: 7468-7485, 2003.
225. Floridi, A., Bruno, T., Miccadei, S., Fanciulli, M., Federico, A., and Paggi, M. G. Enhancement of doxorubicin content by the antitumor drug lonidamine in resistant Ehrlich ascites tumor cells through modulation of energy metabolism. Biochem Pharmacol, 56: 841-849, 1998.
226. Batrakova, E. V., Li, S., Elmquist, W. F., Miller, D. W., Alakhov, V. Y., and Kabanov, A. V. Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. Br J Cancer, 85: 1987-1997, 2001.
227. Illidge, T. M., Cragg, M. S., Fringes, B., Olive, P., and Erenpreisa, J. A. Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage. Cell Biol Int, 24: 621-633, 2000.
228. Stewart, Z. A., Mays, D., and Pietenpol, J. A. Defective G1-S cell cycle checkpoint function sensitizes cells to microtubule inhibitor-induced apoptosis. Cancer Res, 59: 3831-3837, 1999.
229. Mingo-Sion, A. M., Marietta, P. M., Koller, E., Wolf, D. M., and Van Den Berg, C. L. Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene, 23: 596-604, 2004.
230. Lanzi, C., Cassinelli, G., Cuccuru, G., Supino, R., Zuco, V., Ferlini, C., Scambia, G., and Zunino, F. Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells. Prostate, 48: 254-264, 2001.
231. Suzuki, A., Tsutomi, Y., Akahane, K., Araki, T., and Miura, M. Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IPA gene family ILP. Oncogene, 17: 931-940, 1998.
232. Suzuki, A., Tsutomi, Y., Yamamoto, N., Shibutani, T., and Akahane, K. Mitochondrial regulation of cell death: mitochondria are essential for procaspase 3-p21 complex formation to resist Fas-mediated cell death. Mol Cell Biol, 19: 3842-3847, 1999.
233. Basu, A. and Haldar, S. Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. FEBS Lett, 538: 41-47, 2003.
234. Blagosklonny, M. V. and Fojo, T. Molecular effects of paclitaxel: myths and reality (a critical review). Int J Cancer, 83: 151-156, 1999.
235. Tsang, W. P., Chau, S. P., Kong, S. K., Fung, K. P., and Kwok, T. T. Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci, 73: 2047-2058, 2003.
236. Liang, B. C. and Ullyatt, E. Increased sensitivity to cis-diamminedichloroplatinum induced apoptosis with mitochondrial DNA depletion. Cell Death Differ, 5: 694-701, 1998.
237. Liu, C. Y., Lee, C. F., Hong, C. H., and Wei, Y. H. Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. Ann N Y Acad Sci, 1011: 133-145, 2004.
238. Jiang, S., Cai, J., Wallace, D. C., and Jones, D. P. Cytochrome c-mediated apoptosis in cells lacking mitochondrial DNA. Signaling pathway involving release and caspase 3 activation is conserved. J Biol Chem, 274: 29905-29911, 1999.
239. Park, S. Y., Chang, I., Kim, J. Y., Kang, S. W., Park, S. H., Singh, K., and Lee, M. S. Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem, 279: 7512-7520, 2004.