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Title: MBD genes and Hedgehog signalling in cancer
Author: Zhu, Yanhua
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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In this study, two sets of candidate genes in colon and lung cancer tumourigenesis were studied. The first set comprised members of a family of genes whose proteins are important in the recognition of the methylation/epigenetic status of other genes. The second set were members of a pathway that normally regulate tissue development but whose abnormal, epigenetic loss of activity could lead to tissue dysregulation and tumourigenesis. MBD3 and MBD2 are two members of the MBD family of proteins with a methyl-CpG-binding domain (MBD) involved in transcriptional silencing of methylated genes. Both genes are located in chromosomal regions that suffer loss of heterozygosity in colon and lung cancers. By SSCP analysis and methylation sensitive restriction followed by PCR, 2 mutations were found in 28 cell lines and in no cases was there evidence of gene silencing by hypermethylation of putative promoter regions. RT-PCR and northern hybridisation showed expression of MBD3 in all cancer cell lines examined. The results indicate that neither MBD2 nor MBD3 are major targets of genetic and epigenetic alteration in colon and lung cancers. The Hedgehog (Hh) pathway is a highly conserved signalling cascade involved in many developmental processes. In this study, two genes of this pathway, SMO and GLI3 were investigated for expression and epigenetic alterations in colon and lung cancers. In three cell lines expression of SMO was absent, the putative SMO promoter was fully methylated and GLI3 was not expressed. Two other cell lines had a methylated wild-type SMO allele and expressed mutant SMO, and also did not express GLI3. The results indicate that SMO is silenced by CpG island hypermethylation in colon and lung cancer cell lines, that GLI3 is also silenced in colon and lung cancer cell lines by an as yet unrevealed mechanism and that GLI3 is possibly regulated by SMO in a manner outside the normal sequence of steps currently thought to comprise the Hh pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available