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Isolation of a Novel Human Gene, APCDD1, as a Direct Target of the ß-Catenin/T-Cell Factor 4 Complex with Probable Involvement in Colorectal Carcinogenesis¹

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [M. T., M. F., Y. F., R. H., T. S., N. M., Y. N.], and Department of Surgery II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan [M. F., M. O.]

To clarify the molecular mechanisms of human carcinogenesis associated with abnormal ß-catenin/T-cell factor (Tcf) signaling, we have been using cDNA microarrays to search for genes whose expression is significantly altered after introduction of wild-type APC into SW480 colon cancer cells. These experiments identified a novel human gene, termed APCDD1, that was down-regulated in the cancer cells by exogenous wild-type APC; its expression was also reduced in response to transduction of AXIN1. Moreover, we documented elevated expression of APCDD1 in 18 of 27 primary colon cancer tissues compared with corresponding noncancerous mucosae. A reporter gene assay using the 5'-flanking region of APCDD1 indicated that transfection of ß-catenin together with wild-type Tcf4 into HeLa cells increased the reporter activity through two putative Tcf/lymphoid enhancer factor-binding motifs upstream of the transcription start site, indicating that APCDD1 is one of the direct targets of this transcription complex. Exogenous APCDD1 promoted growth of colon cancer cells both in vitro and in vivo, whereas transfection with antisense S-oligodeoxynucleotides decreased cell/tumor growth. These data suggest that APCDD1 is directly regulated by the ß-catenin/Tcf complex and that its elevated expression is likely to contribute to colorectal tumorigenesis.

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