Role of hypoxia-induced ADAM 10 in colorectal cancer progression

Todd, Anna Elizabeth

Biological sciences
April 2016

Thesis or dissertation

© 2016 Anna Elizabeth Todd. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is the second deadliest form of cancer within the UK. The majority of CRC arises sporadically, as a result of epigenetic alterations transforming normal epithelium to malignant adenocarcinoma. CRC is highly metastatic and as a solid state tumour possesses regions of hypoxia, which promote metastasis. There is evidence for the involvement of the A Disintegrin And Metalloproteinase (ADAM) family in cancer progression and the hypoxic tumour microenvironment, however ADAM 10 is one of the least characterised members in the context of hypoxia-mediated cancer progression. ADAM 10 is strongly implicated in the regulation of normal colon biology, with an ADAM 10 knockout mouse model displaying embryonic lethality. Therefore, ADAM 10 is a key target of CRC research, to determine what effect hypoxia has on ADAM 10 and what implications this may have in the context of CRC progression.

In this study, CRC cell lines were examined to characterise the effects of severe hypoxia on ADAM 10. Exposure to severe hypoxia induced an alteration to ADAM 10 expression at both protein and transcript levels, with a previously un-reported doublet band seen for mature ADAM 10 at protein level. The doublet is believed to be a hypoxia-mediated post-translational modification, potentially through alterations in ADAM 10 glycosylation. No effects of either severe hypoxia or ADAM 10 knockdown were seen on CRC cellular migration. However, a downregulation in cellular viability was observed in HCT116 cells after ADAM 10 knockdown, independently of hypoxia, indicating a role of ADAM 10 in the regulation of CRC cell viability. Attempts to elucidate the underlying mechanisms behind this revealed a role for ADAM 10 in the regulation of c-MYC and CCND1 expression in HCT116 cells, however no effect on cell cycle progression was observed after ADAM 10 knockdown. This study has identified an important role for ADAM 10, independently of hypoxia, in the regulation of CRC viability, which may promote the progression and metastasis of CRC.

Department of Biological, Biomedical and Environmental Sciences, The University of Hull
Pires, Isabel M.; Greenman, John (Professor of tumour immunology)
Sponsor (Organisation)
University of Hull
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