The role of transcription factor caudal-related homeobox transcription factor 2 in colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most malignant tumors in humans and causes mass mortality. In the age of precise medicine, more and more subtypes of CRC were classified. The caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor which is implicated in differentiation, proliferation, cell-adhesion, and migration. The loss of CDX2 in immunohistochemical stain was reported to be a prognostic factor of colon cancer, but the clinical application remained controversial. Most of the CRCs expressed or over-expressed CDX2. Homeobox genes can display either an oncogenic or a tumor-suppressing activity. CDX2 regulates the developing intestinal epithelium and CRC by different pathways. The complex regulation of CDX2 and its complex targets cause the difficulties of application for CDX2 in the prediction of prognosis. However, CDX2 is a potential biomarker applied in the precise classification of CRC for personalized medicine. This review partially clarifies the role of CDX2 in CRC.

Keywords: Cancer biomarker; Caudal-related homeobox transcription factor 2; Colorectal cancer.

Figure 1

Caudal-related homeobox transcription factor 2 plays different roles in embryo, intestinal epithelium and colorectal cancers. (a) In blastocyst, caudal-related homeobox transcription factor 2 determines the gut development by downregulation of Oct 4 and Nanog. In the intestinal epithelial cell, caudal-related homeobox transcription factor 2 could both promote and inhibit proliferation to maintain the renewal of the intestinal epithelium. (b) In the colorectal cancer cells, caudal-related homeobox transcription factor 2 downregulates the Wnt pathway and prevents G1-S cell cycle transition. Overexpression of caudal-related homeobox transcription factor 2 decreases the epithelial mesenchymal transition. Caudal-related homeobox transcription factor 2 protein binds to ATM and prevents DNA double strand break repair in colorectal cancer cells

Figure 2

Caudal-related homeobox transcription factor 2 regulates the cell cycle in colorectal cancer. Caudal-related homeobox transcription factor 2 carries out the different mechanisms to control the cell cycle. Black and red lines indicate that caudal-related homeobox transcription factor 2 regulates the cell cycle through the transcriptional and non-transcriptional functions, respectively. Caudal-related homeobox transcription factor 2 can not only inhibit but also promote the G1-S cell cycle transition. Caudal-related homeobox transcription factor 2 downregulates cyclin-dependent kinase inhibitor 2D and in turn inhibits Cdk4/6

Figure 3

Caudal-related homeobox transcription factor 2-loss cells and the microenvironment strongly influence each other. The caudal-related homeobox transcription factor 2 knock-out cells induce tumorigenesis of the caudal-related homeobox transcription factor 2 heterozygous cells via inducible nitric oxide synthase and NF-κB signalings. Caudal-related homeobox transcription factor 2 actively makes the microenvironment to be more tumorigenic. The caudal-related homeobox transcription factor 2 expression of colorectal cancer cells can be passively suppressed by the hypoxia-inducible factor-1α, tumor necrosis factor-1α and type I collagen, which are released by the microenvironment

Figure 4

Caudal-related homeobox transcription factor 2 expression of colorectal cancer depends on its microenvironment. The fresh resected colorectal cancer displays different caudal-related homeobox transcription factor 2 expression in cecum and subcutis, indicating that the caudal-related homeobox transcription factor 2 expression of colorectal cancer cells is regulated by the microenvironment