Date of Award

2014

Degree Type

Thesis

Degree Name

Bachelor of Science (Human Biology) Honours

School

School of Medical Sciences

Faculty

Health, Engineering and Science

First Advisor

Dr Peter Dallas

Second Advisor

Professor Mel Ziman

Abstract

Medulloblastoma is the most common malignant childhood brain tumour, and the most significant cause of childhood cancer-related mortality. Recently four core molecular medulloblastoma sub-groups have been identified, with distinct pathogenesis and responses to therapies. Current therapies, do not account for this molecular variation, and many patients may receive inappropriate treatment. To address this, targeted therapies for each molecular sub-group would be ideal. Unfortunately, for the more aggressive Group 3 and Group 4 subgroups, the underlying mechanisms of pathogenesis remain poorly understood. The current challenge is to identify the key tumour suppressors or oncogenes involved in Group 3 and Group 4 pathogenesis, which may ultimately lead to the development of new therapeutic

targets.

Transcriptional profiling studies of medulloblastoma have identified numerous genes commonly affected in other cancers, which may also contribute to medulloblastoma pathogenesis. One potential candidate is Dachshund Homolog 1 (DACH1), which has upregulated expression across all medulloblastoma sub-groups, relative to normal cerebellum, consistent with a potential oncogenic role. This up-regulation is most significant in the Group 4 tumours and is consistent with recent methylation profiling analyses, correlating increased DACH1 expression with gene hypomethylation. This combined evidence suggests that DACH1 may be a medulloblastoma oncogene. Oncogenic over-expression of DACH1 has been demonstrated in both ovarian and colorectal cancers, and is associated with cancer progression and invasiveness, but has not previously been linked to medulloblastoma pathogenesis. Additionally the mechanisms associated with over-expression of DACH1 have not been explored in any cancers; however epigenetic modulation is likely, as DACH1 mutations are relatively rare in most cancer types, and DACH1 mutations in medulloblastoma have not been identified.

Deregulated expression of numerous microRNAs has been identified in various cancers, including medulloblastoma, demonstrating the role of microRNAs in cancer initiation and progression. MicroRNAs provide a potential epigenetic mechanism for regulation of DACH1. Analysis of the DACH1 3’UTR using TargetScan revealed a potential binding sites for nine individual/clusters of miRNAs (Figure 10). One putative miRNA is miR-200b, belonging to the highly conserved microRNA-200 family (miR-200). miR-200 is frequently down-regulated in metastatic cancers, raising the possibility that the miR-200 family may play a role in the pathogenesis of metastatic Group 4 medulloblastoma.

There is an apparent association between high levels of DACH1 expression and low level of miR-200b, and in silico analysis using TargetScan identified a putative binding site for miR- 200b within the DACH1 3’-UTR at nucleotides 971-978. Previous evidence supports the role of both DACH1 and miR-200b in metastatic progression; however an association between the two has not previously been described. Here we propose that deregulated DACH1 was associated with loss of regulation by miR-200b, and demonstrated an inverse correlation between DACH1 and mir-200b expression in representative medulloblastoma cell lines, which was further assessed.

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