EXPRESSION OF THE CDX1 AND CDX2 HOMEOTIC GENES LEADS TO REDUCED MALIGNANCY IN COLON CANCER-DERIVED CELLS

We have previously described an inverse relationship between Cdx1 and Cdx2 mRNA levels and the extent of dysplasia and severity of clinical outcome in colorectal carcinoma, suggesting that altered expression of these genes was associated with colorectal carcinogenesis or tumor pr ogression. To investigate further their involvement in the physiopatho logy of colorectal cancer, HT29 colon carcinoma cells that show very l ow Cdx expression were transfected with Cdx1 and/or Cdx2 cDNA to elici t their overexpression, Growth rate, tumorigenicity, resistance to apo ptosis, and migration potential of the corresponding cells mere analyz ed. Growth rate of cells overexpressing Cdx2 decreased by half, wherea s overexpression of Cdx1 had no effect. However, cells overexpressing both Cdxs had a growth rate reduced to 20% of control. In cells overex pressing Cdx1 or Cdx2, tumorigenicity and resistance to apoptosis indu ced by serum starvation, ceramide, or staurosporine were not changed c ompared with control cells; yet phorbol ester-stimulated cell migratio n was decreased by 50%, In cells overexpressing both Cdx1 and Cdx2, tu morigenicity was decreased by 50%, resistance to apoptosis was signifi cantly lowered, and stimulated cell migration was further decreased to 15% of control compared with cells expressing Cdx1 or Cdx2, Finally, cells overexpressing both Cdxs showed strongly decreased Bcl-2 express ion, which could account for their increased sensitivity to apoptosis, These findings show that, in HT29 cells, both Cdx1 and Cdx2 genes mus t be expressed to reduce tumorigenic potential, to increase sensitivit y to apoptosis, and to reduce cell migration, suggesting that the two genes control the normal phenotype by independent pathways. This may e xplain why loss of Cdx1 or Cdx2 expression is associated with tumor de velopment and invasiveness in colorectal tumors.