The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas.
OBJECTIVE
The current paradigm suggests that the homeodomain transcription factor Cdx2, which directs the development and maintenance of the intestinal epithelium, is a tumor suppressor in the colon and rectum. Although a cardinal property of tumor suppressors is their inactivation during carcinogenesis, the expression of Cdx2 in colorectal tumors has not been compared with that in normal mucosa. Here, Cdx2 expression and function was quantified in tumors and matched normal mucosa from patients with colorectal cancer.


METHODS
Cdx2 expression was quantified by reverse transcription-PCR, immunoblot analysis, and immunohistochemistry. Transcriptional activity was explored by quantifying expression of an endogenous downstream target of Cdx2, guanylyl cyclase C (GCC), in tissues by quantitative reverse transcription-PCR and expression of exogenous Cdx2-specific luciferase promoter constructs in epithelial cells isolated from tumors and normal mucosa.


RESULTS
Most (>80%) colorectal tumors overexpressed Cdx2 mRNA and protein compared with normal mucosa, with median fold increases of 3.6 and 1.4, respectively (P<0.002). Concomitantly, immunohistochemistry revealed elevated levels of Cdx2 in nuclei of tumor cells compared with normal epithelial cells. Further, tumors exhibited increased expression of GCC compared with normal mucosa. Moreover, cells isolated from tumors overexpressed a Cdx2-specific luciferase promoter construct compared with normal mucosal cells.


CONCLUSIONS
These observations show, for the first time, the structural and functional overexpression of Cdx2 by human colorectal tumors compared with matched normal mucosa. They suggest that loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors.
Witek
Matthew E
ME
Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Nielsen
Karl
K
Walters
Rhonda
R
Hyslop
Terry
T
Palazzo
Juan
J
Schulz
Stephanie
S
Waldman
Scott A
SA
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000071616:CDX2 Transcription Factor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D018000:Receptors, Peptide; D025521:Tumor Suppressor Proteins; D008156:Luciferases; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled