The role of PROM-1/CD/AC133 in colorectal cancer.
Abstract
Background: Colorectal cancer is the result of dysregulation within classic regulatory
pathways in epithelial stem-cell(s): the precursors giving rise to all other intestinal
lineages. The resulting cancer stem-cell (CSC) generates tumours utilising its innate
properties, e.g. self-renewal and lineage plasticity. CSCs appear to persist within a
tumour as a distinct subtype responsible for local recurrence/metastasis. Therefore,
therapies targeting colorectal CSCs may lead to improved cancer-specific outcome
measures. The PROM-1/CD/AC133 cell surface marker has been associated with
colorectal CSCs and its expression is reported as an independent negative prognostic
marker. Therefore, this thesis sought to investigate the role of PROM-1/CD/AC133 in
colorectal cancer.
Methods: Tissue-culture, RT-qPCR, IHC, Western blotting, siRNA, PCR-array and
FACS analyses were used to quantify and profile mRNA/protein expression patterns.
Results: PROM-1/CD/AC133 was widely expressed in patient-matched colorectal
tumour, adjacent normal epithelium, vascular invasion, lymph node metastases with
significantly decreased expression in liver metastases. Furthermore, PROM-
1/CD/AC133 expression was not found to enrich colorectal cancer cell line
populations for additional stem cell phenotypes (expression of ABCB1/ABCG2/BMIJ
Murphy 1/CD44/LGR5/MSI-1). The data confirm the presence of alternative splice variants of
PROM-1, and show that transcripts specifying PDZ binding predominate in colorectal
cancer cell lines. Concomitantly, siPROM-1 was shown to modulate the expression
of several key transcripts in colorectal tumourigenesis as well as regulate signal
transduction pathways including the central cancer, colorectal cancer, NF-kB and p53
signalling cascades.
Conclusions: PROM-1/CD/AC133 does not identify rare colorectal cancer cells
responsible for tumourigenesis. However, it is associated with the regulation of
signalling networks associated with cell growth, differentiation and apoptosis
suggesting a potential role for this marker in colorectal tumourigenesis. The
identification of specific target genes and signalling pathways in this thesis provides a
springboard for further investigations into the functional role of this marker in
colorectal cancer, with the potential for better treatments for this disease.
Authors
Murphy, JamieCollections
- Theses [4223]