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postgraduate thesis: Promoter DNA methylation of tumour suppressor microRNA genes in multiple myeloma

TitlePromoter DNA methylation of tumour suppressor microRNA genes in multiple myeloma
Authors
Advisors
Issue Date2011
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wong, K. [黃君揚]. (2011). Promoter DNA methylation of tumour suppressor microRNA genes in multiple myeloma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4733151
AbstractMultiple myeloma (MM) is an incurable haematological malignancy. It is characterized clinically by an asymptomatic precursor stage, known as monoclonal gammopathy of undetermined significance (MGUS), which will transform into symptomatic MM at a rate of 1% per year. Gene promoter hypermethylation by catalytic conversion of cytosine into 5?methylcytosine at promoter?associated CpG island is an alternative mechanism of gene inactivation. MicroRNA (miRNA) is a class of short, single?stranded, non?coding RNA molecules, which will repress the expression of target protein by sequence?specific binding to the three prime untranslated region of the corresponding messenger RNA. In carcinogenesis, miRNA can be either oncogenic when tumour suppressor genes are targeted, or tumour suppressive when oncogenes are targeted. Despite reports of hypermethylation of multiple protein?coding tumour suppressor genes, little is known about DNA methylation of non?coding tumour suppressor miRNA genes in MM. This thesis aimed to investigate the role of promoter hypermethylation of tumour suppressor miRNA genes in MM using a candidate miRNA approach. Moreover, the prognostic significance of tumour suppressor miRNA hypermethylation was studied in a uniformly?treated cohort of MM patients. The role of DNA methylation at the promoter of miR?203, miR?34a, miR?34b/c, miR?124?1, miR?129?2 and miR?224 were studied in MM. The tumour suppressor role of miR?34b/c, miR?124?1, miR?203 and miR?224 were demonstrated in human myeloma cell lines (HMCLs). In particular, restoration of miR?203 in MM cells was shown to inhibit cellular proliferation via targeting and hence direct downregulation of a proto?oncogene, cyclic AMP responsive element binding protein. There are several observations in primary MM samples. First, there was frequent methylation of miR?129?2, miR?203 and miR?224 but infrequent methylation of miR?34a, miR?34b/c and miR?124?1 in MM at diagnosis. Second, tumour?specific hypermethylation of each of the miR?203 and miR?224 promoters was detected at comparable frequencies in MGUS, diagnostic and relapsed/progressed MM, and hence implicated as an early event in myelomagenesis. Thirdly, miR?129?2 methylation was more frequent in diagnostic MM than MGUS, and hence implicated in MGUS progression to MM. On the other hand, despite rare miR?34b/c methylation at diagnosis, miR?34b/c methylation was frequent at relapse/progression, thereby implicating miR?34b/c methylation in MM relapse/progression. Fourthly, despite frequent miR?124?1 methylation in HMCLs, miR?124?1 methylation was rare in both diagnostic and relapsed MM marrow samples, suggesting that miR?124?1 methylation was acquired during in vitro cell culture. Finally, the prognostic significance of methylation of a panel of tumour suppressor miRNAs was studied in a uniformly?treated cohort of MM patients, which revealed that miR?224 hypermethylation as an independent favourable prognostic factor for survival. In conclusion, hypermethylation of tumour suppressor miRNAs is implicated in the pathogenesis (miR?203, miR?129?2, miR?224), progression (miR?34b/c), and prognostification (miR?224) of MM.
DegreeDoctor of Philosophy
SubjectDNA - Methylation.
Small interfering RNA.
Antioncogenes.
Multiple myeloma - Genetic aspects.
Dept/ProgramMedicine

 

DC FieldValueLanguage
dc.contributor.advisorChim, JCS-
dc.contributor.advisorJin, D-
dc.contributor.advisorLiang, RHS-
dc.contributor.authorWong, Kwan-yeung.-
dc.contributor.author黃君揚.-
dc.date.issued2011-
dc.identifier.citationWong, K. [黃君揚]. (2011). Promoter DNA methylation of tumour suppressor microRNA genes in multiple myeloma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4733151-
dc.description.abstractMultiple myeloma (MM) is an incurable haematological malignancy. It is characterized clinically by an asymptomatic precursor stage, known as monoclonal gammopathy of undetermined significance (MGUS), which will transform into symptomatic MM at a rate of 1% per year. Gene promoter hypermethylation by catalytic conversion of cytosine into 5?methylcytosine at promoter?associated CpG island is an alternative mechanism of gene inactivation. MicroRNA (miRNA) is a class of short, single?stranded, non?coding RNA molecules, which will repress the expression of target protein by sequence?specific binding to the three prime untranslated region of the corresponding messenger RNA. In carcinogenesis, miRNA can be either oncogenic when tumour suppressor genes are targeted, or tumour suppressive when oncogenes are targeted. Despite reports of hypermethylation of multiple protein?coding tumour suppressor genes, little is known about DNA methylation of non?coding tumour suppressor miRNA genes in MM. This thesis aimed to investigate the role of promoter hypermethylation of tumour suppressor miRNA genes in MM using a candidate miRNA approach. Moreover, the prognostic significance of tumour suppressor miRNA hypermethylation was studied in a uniformly?treated cohort of MM patients. The role of DNA methylation at the promoter of miR?203, miR?34a, miR?34b/c, miR?124?1, miR?129?2 and miR?224 were studied in MM. The tumour suppressor role of miR?34b/c, miR?124?1, miR?203 and miR?224 were demonstrated in human myeloma cell lines (HMCLs). In particular, restoration of miR?203 in MM cells was shown to inhibit cellular proliferation via targeting and hence direct downregulation of a proto?oncogene, cyclic AMP responsive element binding protein. There are several observations in primary MM samples. First, there was frequent methylation of miR?129?2, miR?203 and miR?224 but infrequent methylation of miR?34a, miR?34b/c and miR?124?1 in MM at diagnosis. Second, tumour?specific hypermethylation of each of the miR?203 and miR?224 promoters was detected at comparable frequencies in MGUS, diagnostic and relapsed/progressed MM, and hence implicated as an early event in myelomagenesis. Thirdly, miR?129?2 methylation was more frequent in diagnostic MM than MGUS, and hence implicated in MGUS progression to MM. On the other hand, despite rare miR?34b/c methylation at diagnosis, miR?34b/c methylation was frequent at relapse/progression, thereby implicating miR?34b/c methylation in MM relapse/progression. Fourthly, despite frequent miR?124?1 methylation in HMCLs, miR?124?1 methylation was rare in both diagnostic and relapsed MM marrow samples, suggesting that miR?124?1 methylation was acquired during in vitro cell culture. Finally, the prognostic significance of methylation of a panel of tumour suppressor miRNAs was studied in a uniformly?treated cohort of MM patients, which revealed that miR?224 hypermethylation as an independent favourable prognostic factor for survival. In conclusion, hypermethylation of tumour suppressor miRNAs is implicated in the pathogenesis (miR?203, miR?129?2, miR?224), progression (miR?34b/c), and prognostification (miR?224) of MM.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B47331513-
dc.subject.lcshDNA - Methylation.-
dc.subject.lcshSmall interfering RNA.-
dc.subject.lcshAntioncogenes.-
dc.subject.lcshMultiple myeloma - Genetic aspects.-
dc.titlePromoter DNA methylation of tumour suppressor microRNA genes in multiple myeloma-
dc.typePG_Thesis-
dc.identifier.hkulb4733151-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4733151-
dc.date.hkucongregation2012-

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