| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 92 === 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.
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