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Title: The role of the 0 type cyclins in colorectal cancer progression
Author: Sarkar, Rupa
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Despite advances in treatment, colorectal cancer remains a major cause of cancer related morbidity and mortality. Although the overall mortality continues to improve, a significant proportion of patients still succumb to the disease. Immunohistochemical analysis of a set of tissue microarray slides obtained from patients with colorectal cancer demonstrated elevated expression of the 0 type cyclins. Expression of cyclin 02 and 03 but not 01 at the invading margin of colon cancer was associated with vascular and lymphatic invasion and an adverse prognosis. This expression did not correlate to the expression of Ki-67 which is a marker of proliferation. In order to understand this association in vitro experiments were carried out in colorectal derived cell lines (LaVa 39 and HRT18). The functional role of the D type cyclins was evaluated by abrogation of individual transcripts using short interfering RNAs. Although a short lived reduction of proliferation was seen in both cell lines with abrogation of the cyclin 01 transcript, no such effect was noted on cell apoptosis. Significant reduction in cell invasion was noted with all three 0 type cyclins, although most notably with cyclin D2 in LaVa 39. The effect of a hypoxic microenvironment on the 0 type cyclins was evaluated to simulate the assumed metabolic conditions of the tumour margin. Prolonged hypoxia resulted in the reduced expression of all three D type cyclins. along with HIF1 and HIF2. Expression of cyclin D1 and cyclin D2 were found to be downregulated following abrogation of HIF1 and HIF2 respectively. In view of the influences of the 0 type cyclins on cell invasion and prognosis, their role in the process of epithelial mesenchymal transition (EMT) was interrogated. LlM1863 cells can be transfoll11ed from epithelial organoid form to mesenchymal like monolayers by TGF-J3, and were utilised as a model of EMT. The expression of the 0 type cyclins was increased following mesenchymal transition. No change in phenotype was noted following siRNA mediated abrogation of the 0 type cyclins in pre and post EMT celis. Unlike the effect in LoVo 39 and HRT18 cell lines, reduced 0 type cyclins had no effect on proliferation. However similar to the LoVa 39 cells, reduced 0 type cyclins were associated with a small but significant reduction in cell invasion. This led us to hypothesise that although the 0 type cyclins may not be involved in induction or maintenance of EMT, they may be a part of the EMT program and contribute to metastatic progression by facilitating cell invasion. Further work in in vivo models is required to clarify this hypothesis. However, these results indicate that the 0 type cyclins have clinical potential both as a prognostic marker and as a therapeutic target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available