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This dissertation, Characterization of Mitotic Checkpoint Proteins, MAD1 and MAD2, in Hepatocellular Carcinoma by Man-fong, Sze, 施敏芳, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Characterization of Mitotic Checkpoint Proteins, MAD1 and MAD2, in Hepatocellular Carcinoma Submitted by Sze Man Fong For the degree of Doctor Philosophy at the University of Hong Kong in September 2006 Chromosomal instability (CIN) refers to high rates of chromosome gains and losses and is a major cause of genomic instability. Recurrent chromosomal alterations have been commonly found in hepatocellular carcinoma (HCC), which is a prevalent cancer worldwide and also in Southeast Asia and Hong Kong. These frequent gains and losses of chromosomes suggest that CIN contributes to hepatocarcinogenesis. One major mechanism for CIN is through the loss of mitotic spindle checkpoint. In this study, we have identified a novel splicing variant of MAD1, which we named MAD1β and had deletion of exon 4. There was differential subcellular localization in that MAD1β localized in the cytoplasm whereas the original full-length form MAD1 localized in the nuclei. Expression of mRNA of MAD1β was detected in all of the 11 HCC cell lines tested and in most of the human HCC samples and some of their corresponding nontumorous livers tested. MAD1β was able to interact with and alter the localization of MAD2 in cells. MAD1β tably expressing hepatoma cell lines had reduced MAD2 protein expression, mitotic checkpoint competence, and more spread-out ranges of chromosome numbers as compared with the corresponding vector controls and parental cell lines. Moreover, the lower MAD2 protein expression in MAD1β-over-expressing cell line was found to be related to physical interaction between MAD1β and MAD2. However, the mechanism on the alteration of the MAD2 protein level in hepatoma cells needs to be further investigated. On the other hand, under-expression of MAD2 protein significantly correlated with mitotic checkpoint incompetence in HCC cell lines. However, over-expression of MAD2 was observed in 32% of our human HCC and was significantly associated with direct liver invasion by tumor and tended to correlate with tumor microsatellite formation, which indicate a more aggressive tumor behavior. Besides MAD2, MAD1 mRNA was also over-expressed in 38% of our human HCC. However, the significance of over-expression of MAD1 mRNA in hepatocarcinogenesis needs to be further investigated. Taken together, our results have demonstrated that over-expression of MAD1β was able to lower MAD2 expression, change the localization MAD2 from nuclear to cytoplasmic and down-regulation of MAD2, and result in mitotic checkpoint defect in HCC. The data suggest that both MAD1β and MAD2 play a significant role in mitotic checkpoint control and in hepatocarcinogenesis. An abstract of exactly 371 words DOI: 10.5353/th_b3843855 Subjects: Spindle (Cell division)Chromosome abnormalitiesLiver - Cancer - Genetic aspectsCarcinogenesis

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