Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood.
However, consistent with a role for dominant repression mechanisms in CDX2 silencing, all somatic cell hybrids resulting from pairwise fusions between colon cancer lines with intact CDX2 expression and lines lacking CDX2 had reduced CDX2 transcripts and protein.
Furthermore, CDX2 was found to co-immunoprecipitate with the p65 subunit of NF-kappaB and to inhibit p65-induced NF-kappaB minimal promoter activity in colon cancer cells.
In order to elucidate further the molecular mechanisms underlying this phenomenon, we first hypothesized that Cdx1 or Cdx2 expression reduces colon cancer cell proliferation by inhibiting beta-catenin/T-cell factor (TCF) transcriptional activity.
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.
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.
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.
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.
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(-).
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.
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.
Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2.
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.
In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003).
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.