Change of DNA methylation is a hallmark of cancer. It is frequently associated with cancer progression. Testicular germ cell tumor (TGCT) is the most common malignant tumor in young males. Currently, only a limited number of genes are known to be epigenetically changed in TGCT. Genome-wide analysis of differential methylation in a previously established testicular cell line is documented here. A total of 35,208 differentially methylated regions (DMR) were identified. However, only a small number of DMRs mapped to gene promoters. Genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. Several candidate genes ( APOLD1, PCDH10 and RGAG1) were found to be dysregulated in TGCT patients. Surprisingly, APOLD1 was mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. / The majority of DMRs are located in introns or intergenic regions, but their functions are not well understood. Some of these DMRs were found to regulate non-coding RNAs (ncRNAs). In this study, differential methylation of 3 small nucleolar RNAs (snoRNA) and 3 microRNAs (miRNA) were identified. One of the miRNAs, miR-199a, is embedded in a conserved region in intron-14 of dynamin 3 at 1q24.3. Hypermethylation of miR-199a correlated with testicular cancer progression, and silencing of miR-199a. Re-expression of miR-199a in testicular cancer cells suppressed cell growth, cancer migration, invasion, and metastasis. miR-199a-5p, one of two mature miRNA species derived from miR-199a, is associated with cancer progression. An embryonal carcinoma antigen, podocalyxin-like protein 1 (PODXL), was identified to be a target of miR-199a-sp. PODXL is an anti-adhesive protein overexpressed in aggressive testicular cancer. Knockdown of PODXL suppressed cancer invasion. The inverse relationship between PODXL and miR-199a-5p expression suggests that PODXL is one of the downstream effectors mediating cancer invasion and metastasis. This study links DNA methylation, miR-199a dysregulation, and PODXL expression as a mechanism to explain testicular cancer progression. / Cheung, Hoi Hung. / Adviser: Woi-Yee Chan. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 165-192). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy