Immunohistochemical studies showed that the liver tumor and primary colon cancer were negative for cytokeratin (CK) 7 and positive for CK20 and Caudal-type homeobox transcription factor 2 (CDX-2).
Immunostaining showed that the colon cancer was positive for CDX2, SATB2, had a loss of PMS2 and intact expression of MLH1, MSH2 and MSH6, negative for AMACR, while the prostate cancer was positive for AMACR, had intact expression of PMS2, MLH1, MSH2 and MSH6, and negative for CDX2 and SATB2.
We also show that HNF4<i>α</i> and CDX2 are required for the expression of these UGT genes in colon cancer cell lines, and show robust correlation of UGT expression with CDX2 and HNF4<i>α</i> levels in normal human colon.
The transcriptional regulation of the VTI1A-TCF4 fusion gene was investigated in LS174T cells where the activity of the VTI1A promoter was compared to that of the TCF7L2 promoter, and the transcription factor CDX2 was analyzed for gene regulatory activity of the VTI1A promoter through luciferase reporter gene assay using colon cancer cell lines as a model.
Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer.
Although the lack of CDX2 expression has recently been proposed as a potential biomarker for a high risk of relapse in patients with stage II and III colon cancer after complete surgical resection, its prognostic role in metastatic colorectal cancer (CRC) remains unclear and warrants investigation.
The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis, also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut.
Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2.
We found that the colon cancer cell lines HCT-116 and HCT-15 exhibited a confluence-dependent increase in CD26 mRNA and protein, associated with decreased expression of c-Myc, increased USF-1 and Cdx 2 levels, and unchanged HNF-1α expression.
Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27Kip1, whereas approximately 68% of high-CDX2 lesions retain expression of p27Kip1.
Immunoprofiling of the specimens revealed a rare phenotype: the jejunal cancer was positive for cytokeratin (CK) 7, partially positive for CK20, and Cdx-2-negative, whereas the colon cancer was CK7(+), CK20(-), and Cdx-2(-).
Real-time PCR and western blotting demonstrated that CDX2 expression was decreased by CoCl2 (100 microM) in both SW480 and LS174T cells. mRNA and protein expression of HIF-1alpha and mRNA expression of Snail was increased by hypoxia in both colon cancer cell lines.
However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).
Moreover, this is the first report establishing CDX2 as transactivator of tumor growth-promoting gene expression in colon cancer, adding to untangle the complex and conflicting biological functions of CDX2 in colon cancer and supporting MS4A12 as important factor for normal colonic development as well as for the biology and treatment of colon cancer.
These data provide evidence that Cdx2 antagonizes the process of tumor cell dissemination, and they suggest that this homeobox gene might represent a new therapeutic target against metastatic spreading of colon cancer.
To understand the functional contributions of CDX2 to colon cancer, we disrupted CDX2 in LOVO and SW48 human colon cancer cell lines by targeted homologous recombination.