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- Document type:
- Journal Article; Research Support, Non-U.S. Gov't
- Author(s):
- Herbst, A; Bommer, GT; Kriegl, L; Jung, A; Behrens, A; Csanadi, E; Gerhard, M; Bolz, C; Riesenberg, R; Zimmermann, W; Dietmaier, W; Wolf, I; Brabletz, T; Göke, B; Kolligs, FT
- Title:
- ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.
- Abstract:
- BACKGROUND & AIMS: The ubiquitously expressed basic helix-loop-helix transcription factor ITF-2B has an important role in differentiation processes, and its transcription is regulated by beta-catenin. The ITF-2 gene is located in the chromosomal region 18q21; allelic loss of this locus occurs in 70% of colorectal cancers. We analyzed the expression, regulation, and function of ITF-2B in colorectal carcinogenesis. METHODS: The loss-of-heterozygosity (LOH) status of 18q21 and expression of ITF-2B were studied in colorectal carcinomas using polymerase chain reaction-based methods and immunohistochemistry. The biologic effects of ITF-2B were studied in colorectal cancer cells. Reporter gene assays and chromatin immunoprecipitation were utilized to analyze effects of ITF-2B on gene transcription. RESULTS: ITF-2B is strongly expressed in colon adenomas but frequently down-regulated in carcinomas because of LOH at 18q21. ITF-2B induces cell cycle arrest and regulates the expression of p21(Cip1) via newly identified E-boxes in the CDKN1A gene, independently of p53. Loss of ITF-2B expression correlates with loss of p21(Cip1) expression in primary colon carcinomas. CONCLUSIONS: Accumulation of mutations and allelic losses are driving forces of colorectal carcinogenesis. ITF-2B, which is up-regulated during early colorectal carcinogenesis because of loss of adenomatous polyposis coli, is a target for LOH on chromosome 18q, along with deleted in colorectal carcinoma and Smad4. This finding, along with the fact that ITF-2B is a regulator of the key cell cycle inhibitor p21(Cip1), indicates that ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition.
- Journal title abbreviation:
- Gastroenterology
- Year:
- 2009
- Journal volume:
- 137
- Journal issue:
- 2
- Pages contribution:
- 639-48, 648.e1-9
- Language:
- eng
- Fulltext / DOI:
- doi:10.1053/j.gastro.2009.04.049
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/19394332
- Print-ISSN:
- 0016-5085
- TUM Institution:
- II. Medizinische Klinik und Poliklinik (Gastroenterologie)
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