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Title: The role of the retinoblastoma gene in liver regeneration, polyploidisation and hepatocarcinogenesis
Author: Boyce, Stephen A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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To determine the role of Rb in the regulation of hepatocyte replication, two models of liver regeneration were developed. The first involved the use of carbon tetrachloride, a liver-specific toxin, to cause necrosis. The second involved performing a partial hepatectomy (PH) – a surgical resection of approximately 2/3 of the murine liver. When liver regeneration following either hepatectomy or necrosis occurred in the absence of Rb, the result was deregulated hepatocyte division, with acceleration of hepatocyte proliferation. Loss of Rb also inhibited the normal process of polyploidisation, which usually occurs during regeneration. To determine the role of Rb in liver cancer, a model of hepatocarcinogenesis was developed in employing the DNA damaging agent diethylnitrosamine together with protracted administration of carbon tetrachloride to produce sustained necrosis and regeneration. Loss of Rb was associated with increased levels of apoptosis and the development of preneoplastic foci characteristic of early hepatocarcinogenesis. These foci showed increased staining for markers of proliferation as compared to surrounding liver. Quantification of these foci demonstrated Rb loss was associated with an increase in the frequency, size and total area of preneoplastic tissue. Rb was also associated with increased levels of hepatocyte apoptosis as compared to controls. Taken together these results demonstrate an important role for Rb in the regulation of liver regeneration and polyploidisation. When Rb loss occurs on a background of DNA damage and sustained inflammation, analogous to chronic liver disease, there is an acceleration of the preneoplastic phase of hepatocarcinogenesis suggesting loss of Rb may be a critical factor in the development of liver cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available