Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells

BACKGROUND: The KIAA1199 transcript is upregulated in colon adenomas and downregulated upon beta-catenin knockdown. METHODS: Transcript profiling was performed on >500 colon biopsies, methylation profiling data were compared with transcript data. Immunohistochemistry assessed KIAA1199 protein expression in 270 stage II/III tumours (>3 years follow-up). The effects of stable KIAA1199 knockdown in SW480 cells (three different constructs) were studied using transcriptional profiling, proliferation and protein analysis. RESULTS: The KIAA1199 transcript was strongly upregulated in 95% of adenocarcinomas. Absent expression in normal mucosa correlated with KIAA1199 promotor methylation. Nuclear and cytoplasmic KIAA1199 protein expression was identified in colon adenocarcinomas and other types of cancers. A subpopulation of patients with tumours strongly expressing KIAA1199 in the nucleus showed a better outcome with regard to recurrence as lung or liver metastases. The KIAA1199 knockdown affected the cell cycle and the Wnt-signalling pathway. Reduced cellular proliferation and decreased KI67, phosphorylated retinoblastoma, beta-catenin and ASCL2 protein expression supported these findings. Eighteen Wnt-signalling genes differentially expressed upon KIAA1199 knockdown correlated with the KIAA1199 expression profile in clinical specimens. CONCLUSION: The KIAA1199 knockdown attenuates the effects of the Wnt/beta-catenin signalling and it may thus be regarded as a regulatory part of this pathway. British Journal of Cancer (2011) 105, 552-561. doi:10.1038/bjc.2011.268 www.bjcancer.com Published online 19 July 2011 (C) 2011 Cancer Research UK