The Role of CDX2 in Colon Cancer Development and Progression

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling

Abstract

Colon cancer is one of the most commonly diagnosed forms of cancer, responsible for
approximately 1 in 10 cancer-related deaths worldwide. The molecular mechanisms
behind the development of colon cancer are heterogeneous but nonetheless important in
relation to patient treatment and prognosis. Dysregulation of the intestine specific
transcription factor caudal-related homeobox transcription factor 2 (CDX2) has been
linked to the development and progression of colon cancer. It plays a critical role in the
homeostasis of the heathy colon epithelium, however, the role of CDX2 in colon cancer
development is yet to be determined. Evidence suggests that loss of CDX2 expression
in colon cancer tumors is linked to poor prognosis, but at the same time CDX2 is
regarded as a lineage survival oncogene in colon cancer cell lines. This thesis explores
the role of CDX2 in regulation of gene expression in colon cancer cells and what effect
CDX2 dysregulation may have on the development and progression of colon cancer.
In paper I, a cellular model to investigate effect of a gene of interest was generated by
introducing doxycycline inducible CDX2 expression in the LS174T colon cancer cell
line. Using this model which allows tight control of CDX2 expression, novel target genes
of CDX2 important in colon homeostasis are identified.
The role of CDX2 in regulation of expression of the recurrent colon cancer fusion gene,
VTI1A-TCF7L2, was investigated in paper II. Here we discover that the fusion protein
is a dominant negative regulator of Wnt signaling and that it istranscriptionally regulated
by CDX2, possibly resulting in aberrant expression of a dominant negative version of
TCF7L2.
The surgical stress response is regarded as a risk factor of the recurrence of colon cancer.
Paper III investigates the effect of perioperative serum from patients undergoing colon
cancer surgery on the adhesion abilities of colon cancer cell lines, as well as the effect
of CDX2 expression on adhesion. Colon cancer cells shows increased adhesion abilities
III
in postoperative serum compared to preoperative serum, and the increased adhesion in
the postoperative serum is seen to depend on CDX2 expression.
Together, the results in this thesis aim to elucidate the role of CDX2 both in colon
homeostasis but also in the development and progression of colon cancer. Novel CDX2
target genes are identified, including the colon cancer fusion protein VTI1A-TCF7L2
possibly linked to the development of colon cancer. CDX2 is shown to affect the
adhesion abilities of cultured colon cancer cells, revealing a probable mechanism in
which dysregulation of CDX2 may lead to cancer metastasis.
OriginalsprogEngelsk
Antal sider108
StatusUdgivet - 6 nov. 2020

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