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Tumor Biology |
Division of Gastroenterology, Brigham and Women’s Hospital [R. J. G.], Cancer Biology, Dana-Farber Cancer Institute [R. J. G., H. L. F., Y. L., A. B. P.], Department of Pathology [Y. F.] and Division of Gastroenterology [L. M. S.], Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115
A gene related to cell differentiation was identified by differential
display as a candidate suppressor of metastases in colon cancer. This
gene, with a full-length cDNA of 3 kb, is expressed in normal colon and
primary colon cancer tissues and cell lines but not in their metastatic
counterparts. A GenBank search found that it is identical to a recently
cloned gene, differentiation-related gene-1
(Drg-1), isolated from differentiated HT-29 colon cancer
cells. Stable transfection of the SW620 metastatic colon cancer cell
line with Drg-1 cDNA induced morphological changes
consistent with differentiation and up-regulated the expression of
several colonic epithelial cell differentiation markers (alkaline
phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the
expression of Drg-1 is controlled by several known cell
differentiation reagents, such as ligands of peroxisome
proliferator-activated receptor 
(troglitazone and BRL46593) and of
retinoid X receptor (LG268), and histone deacetylase inhibitors
(trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A
synergistic induction of Drg-1 expression was seen with
the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine
(100 nM), an inhibitor of DNA methylation. Functional
studies revealed that overexpression of Drg-1 in
metastatic colon cancer cells reduced in vitro invasion
through Matrigel and suppressed in vivo liver metastases
in nude mice. We propose that Drg-1 suppresses colon
cancer metastasis by inducing colon cancer cell differentiation and
partially reversing the metastatic phenotype.
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