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

• Published in: British journal of cancer 2011-08, Vol.105 (4), p.552-561
• Main Authors: Birkenkamp-Demtroder, K, Maghnouj, A, Mansilla, F, Thorsen, K, Andersen, C L, Øster, B, Hahn, S, Ørntoft, T F
• Format: Article
• Language: English
• Subjects: 631/136/2091; 631/80/86; 692/699/67/1504/1885/1393; 692/699/67/1857; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Adhesion; Cell cycle; Cell Movement; Cell Proliferation; Colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drug Resistance; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genes; Genomes; Humans; Immunohistochemistry; Medical research; Medical sciences; Microscopy, Fluorescence; Molecular Diagnostics; Molecular Medicine; Neoplasm Staging; Oncology; Protein Array Analysis; Protein expression; Proteins; Proteins - genetics; Proteins - metabolism; Signal Transduction; Software; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription factors; Tumors; Up-Regulation; Wnt Proteins - metabolism
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.268

Background: The KIAA1199 transcript is upregulated in colon adenomas and downregulated upon β -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, β -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/ β- catenin signalling and it may thus be regarded as a regulatory part of this pathway.