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Activated B-catenin regulates the transcription of oncogenic target genes and is critical for tumorigenesis. Because nuclear functions are frequently coupled, we investigated whether it also has a role in alternative splicing of oncogenic genes. We showed that stabilized B-catenin caused alternative splicing of estrogen receptor-B pre-mRNA in colon cancer cells. To establish a direct role of B-catenin in regulated splicing, we selected a high-affinity RNA aptamer that associated with B-catenin in vivo . Nuclear localized aptamer inhibited B-catenin-dependent transcription of cyclin D1 and c-myc in colon cancer cells; thus, cells stably expressing the aptamer exhibited cell cycle arrest and reduced tumor forming potential. Most significantly, the aptamer prevented the alternative splicing induced by stabilized B-catenin. Taken together, our results establish that B-catenin has an important role in both transcription and splicing, and that its action can be modulated by a high-affinity RNA aptamer. The RNA aptamer could be further developed as a specific inhibitor for cancer therapeutics. (Cancer Res 2006; 66(21): 10560-6)