The Role of CDX2 in Colon Cancer Development and Progression

Johanne Davidsen

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
UdgivelsesstedRoskilde
ForlagRoskilde Universitet
Antal sider108
StatusUdgivet - 6 nov. 2020

Bibliografisk note

Vejledere: Jesper T. Troelsen & Ismail Gogenür

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