REVERSION OF UROEPITHELIAL CELL TUMORIGENESIS BY THE ECTOPIC EXPRESSION OF HUMAN WNT-5A

Wnt gene family members are thought to play an important role in cell growth and differentiation. When normal wnt gene expression is disrupt ed, there is the potential for cell transformation. We have found prev iously that a strong correlation exists between the loss of normal wnt -5a gene expression and cell transformation (Olson and Papkoff, Cell G rowth & Differ., 5: 197-206, 1994), Recently, this has been tested dir ectly using antisense wnt-5a, which, when expressed in mouse mammary c ells, results in cell transformation (Olson and Gibe, Antisense wnt-5a transforms C57MG mouse mammary epithelial cells, manuscript in prepar ation). We hypothesize that wnt-5a is a growth-regulating gene, the di sruption of which could result in tumorigenesis. The multistage progre ssion of many human cancers involves the loss of normal tumor suppress or gene(s) activity, Several tumor suppressor genes are thought to map to chromosome 3p11-p25. We have studied the ectopic expression of hum an wnt-5a (3p14-p21) in a tumorigenic uroepithelial cell line with del etion of chromosome 3p13-p21.2. This results in loss of tumorigenicity in athymic nude mice and suppresses anchorage-independent cell growth in soft agar. This suggests that human wnt-5a is a novel tumor suppre ssor gene in uroepithelial cell carcinoma and may be one of the suppre ssor genes deleted or rearranged on chromosome 3p.