MiniSOX9, a dominant-negative variant in colon cancer cells

• Published in: Oncogene Vol. 30; no. 22; pp. 2493 - 2503
• Main Authors: Abdel-Samad, R, Zalzali, H, Rammah, C, Giraud, J, Naudin, C, Dupasquier, S, Poulat, F, Boizet-Bonhoure, B, Lumbroso, S, Mouzat, K, Bonnans, C, Pignodel, C, Raynaud, P, Fort, P, Quittau-Prévostel, C, Blache, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-06-2011; Nature Publishing Group
• Subjects: 631/208/726/649; 631/67/395; 631/80/86; 692/699/67/1504/1885/1393; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Alternative Splicing; Animals; Anti-oncogenes; Apoptosis; Base Sequence; Biological and medical sciences; Cell Biology; Cell Line, Tumor; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Development and progression; Enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Genes, Dominant; Genetic aspects; Genetic variation; Human Genetics; Humans; Hyperplasia; Immunohistochemistry; Internal Medicine; Intestine; Introns; Kinases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Mutant Strains; Molecular and cellular biology; Molecular Sequence Data; mRNA processing; Mutation; Oncology; original-article; Physiological aspects; Post-transcription; Promoter Regions, Genetic; Protein kinase; Protein kinase C; Protein Kinase C-alpha - antagonists & inhibitors; Protein Kinase C-alpha - metabolism; Ribonucleic acid; RNA; RNA-directed DNA polymerase; Rodents; Signal transduction; Sox9 protein; SOX9 Transcription Factor - antagonists & inhibitors; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription factors; Tumors; Wnt protein; Wnt Proteins - metabolism; France; Wnt/β-catenin signaling pathway; PKCα; SOX9; Colonic disease; Variant; Colon cancer; Digestive diseases; Intestinal disease; Malignant tumor; Carcinogenesis; Cell signaling; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.621

Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the
Sox9
gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase–PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the
SOX9
locus gives new insights on its role in colon cancer.