WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors

Wnt family members are critical to many developmental processes, and compon ents of the Wnt signaling pathway have been linked to tumorigenesis in fami lial and sporadic colon carcinomas. Here we report the identification of tw o genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epit helial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together wit h a third related gene, WISP-3, these proteins define a subfamily of the co nnective tissue growth factor family. Two distinct systems demonstrated WIS P induction to be associated with the expression of Wnt-1. These included ( i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 tra nsgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24 .3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in huma n colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tum ors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40 fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 2 0q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expre ssion in colon cancer may play a role in colon tumorigenesis.