Cdx2, short for caudal-related homeobox transcription factor 2, is an intestine-specific nuclear transcription factor. It is crucial in assigning positional identity during embryogenesis and in maintaining intestinal epithelium homeostasis. It is associated with pathways like Wnt/β-catenin, Notch, and is important for processes such as cell proliferation, tissue identity determination, and tumorigenesis. Animal models, especially gene-knockout models, have been valuable in studying its functions [2,3].

In colon cancer cells, CDX2 knockdown promoted cell proliferation in vitro, accelerated tumor formation in vivo, and induced cell cycle transition from G0/G1 to S phase. This was due to the up-regulation of Wnt signaling activity as shown by TOP/FOP-Flash reporter assay, with downstream targets like β-catenin, cyclin D1 and c-myc being up-regulated. Conversely, CDX2 overexpression had the opposite effects. Dual-luciferase reporter and qChIP assays confirmed that CDX2 transcriptionally activates glycogen synthase kinase-3β (GSK-3β) and axis inhibition protein 2 (Axin2) by directly binding to their regulatory regions, thus suppressing Wnt/β-catenin signaling [1].

In animal models, gain of Cdx2 function can cause a posterior shift in tissue identity, modeling intestinal-type metaplasias of the esophagus and stomach, while loss of Cdx2 function can lead to an anterior shift, inducing serrated-type lesions in the colon, which are risk factors for esophageal, stomach, and colon cancer [2]. In colorectal cancer, loss of CDX2 expression, mostly in right-sided, microsatellite-unstable tumors, is associated with aggressive carcinomas and poor prognosis, and can potentially be used as a biomarker for high-risk CRC patients [3,4].

In conclusion, Cdx2 is essential for normal development and tissue homeostasis, especially in the intestinal tract. Gene-knockout and other animal models have revealed its role in suppressing tumorigenesis in the context of colon cancer by modulating key signaling pathways. Understanding Cdx2 functions through these models provides insights into the mechanisms of cancer development and potential prognostic biomarkers for related diseases [1,2,3,4].