CUHK electronic theses & dissertations collection

Deletion on the short arm of chromosome 3 is one of the most important genetic abnormalities in the tumorigenesis of nasopharyngeal carcinoma (NPC). Both physical mapping and functional studies have targeted an NPC-related tumor suppressor gene(s) to chromosome 3p21.3. Our group has previously reported that the Ras Association Domain Family 1A (RASSF1A) gene, located within a 120-kb minimal deleted region on 3p21.3, was frequently inactivated by promoter hypermethylation in NPC. These findings suggest that RASSF1A may be a critical tumor suppressor gene in NPC. In this study, the functions of RASSF1A in NPC was characterized with the following specific aims: (1) the role of RASSF1A as a tumor suppressor in NPC cells; (2) the identification of novel RASSF1A-modulated genes and pathways in NPC; (3) the effect of RASSF1A knockdown in immortalized nasopharyngeal epithelial cells; (4) the aberrant transcription and epigenetic changes of other RASSF family of genes ( RASSFS/NORE1 and RASSF4/AD037) in NPC.In summary, RASSF1A is a major tumor suppressor gene from 3p21.3 in NPC. RASSF1A may exert its tumor suppressor function through various biochemical pathways. The novel findings from this study revealed the role of RASSF1A in the tumorigenesis of NPC. It also led to the better understanding of the molecular pathogenesis of this endemic cancer. (Abstract shortened by UMI.)RASSF1A is a member of the RASSF family of proteins characterized by a consensus Ras-association domain at the C-terminus. The expression and methylation status of two other members of RASSF gene family, RASSF4/AD037 and RASSF5/NORE1, were investigated in NPC. The study showed that RASSF1A, but not other members of the RASSF family, is the target tumor suppressor in this particular cancer type.Restoration of wild-type RASSF1A, by means of transfection, in a RASSF1A-deficient NPC cell line (C666-1) led to marked growth inhibition in the NPC cells. Isolated stable clones expressing RASSF1A demonstrated retarded cell proliferation in vitro . Soft-agar assay showed decreased number and sizes of colonies formed by these clones. The expression of RASSF1A in NPC cells also led to a dramatic reduction in tumorigenic potential in nude mice. The findings provide functional evidence that RASSF1A is a target tumor suppressor gene on 3p21.3 in NPC.Chow Shuk Nga Lillian."May 2005."Adviser: Kwok Wai Lo.Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3588.Thesis (Ph.D.)--Chinese University of Hong Kong, 2005.Includes bibliographical references (p. 112-124).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, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.Abstract in English and Chinese.School code: 1307