Medulloblastoma (MB) is the most common malignant brain tumour in children. MBs arise in the cerebellum, originating from neural stem cells progenitors. It has previously been shown that the lack of integrity of signalling pathways due to genetic alterations play a key role in MB chemosensitivity. An example is the p53 signalling, with p53 mutations and or deletions which are associated with drug resistance. Here, we explored the role of p53 induction by chemotherapeutic drugs such as etoposide in MB and the way to bypass the need for intact p53 to trigger apoptosis. We specifically demonstrated that a downstream miRNA target transcribed by p53, miR-34a, is able to reduce the number of viable cells in cultures of MB cells lacking functional p53, although the effect was limited. Beyond the genetic background of a tumour, it is more and more described that the tumour microenvironment plays a key role in drug resistance. MB is a solid tumour and hence will contain areas deprived in oxygen (hypoxic). It has been widely documented that hypoxia is associated with poor prognosis and resistance to treatment in other cancer models and we here aimed to investigate the specific role of hypoxia in MB response to etoposide. We demonstrated that MB (p53 WT) cell lines became more resistant in chronic but not acute hypoxia and this was associated with a decrease in the recruitment of double strand DNA damage sensing machinery and subsequent impairment to transactivate p53 and transcription of pro-apoptotic genes. A transcriptomic microarray profiling study further revealed that chronic hypoxia induced broad and significant changes in global gene expression affecting many biological pathways including stem cell maintenance, neuronal development and phosphoinositol-3 phosphate kinase.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:617461 |
| Date | January 2013 |
| Creators | Fan, Yuen Ngan |
| Contributors | See, Violaine |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/16933/ |
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