TY - JOUR
T1 - ITF-2 Is Disrupted via Allelic Loss of Chromosome 18q21, and ITF-2B Expression Is Lost at the Adenoma-Carcinoma Transition
AU - Herbst, Andreas
AU - Bommer, Guido T.
AU - Kriegl, Lydia
AU - Jung, Andreas
AU - Behrens, Andrea
AU - Csanadi, Endy
AU - Gerhard, Markus
AU - Bolz, Christian
AU - Riesenberg, Rainer
AU - Zimmermann, Wolfgang
AU - Dietmaier, Wolfgang
AU - Wolf, Isabella
AU - Brabletz, Thomas
AU - Göke, Burkhard
AU - Kolligs, Frank T.
N1 - Funding Information:
Funding Supported by the Deutsche Forschungsgemeinschaft (DFG grants KO1826/3-1 and 3-2, to F.T.K.) and a grant from the Wilhelm-Sander-Stiftung (2003.026.1).
PY - 2009/8
Y1 - 2009/8
N2 - 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 β-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 p21Cip1 via newly identified E-boxes in the CDKN1A gene, independently of p53. Loss of ITF-2B expression correlates with loss of p21Cip1 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 p21Cip1, indicates that ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition.
AB - 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 β-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 p21Cip1 via newly identified E-boxes in the CDKN1A gene, independently of p53. Loss of ITF-2B expression correlates with loss of p21Cip1 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 p21Cip1, indicates that ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition.
UR - http://www.scopus.com/inward/record.url?scp=67650954364&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2009.04.049
DO - 10.1053/j.gastro.2009.04.049
M3 - Article
C2 - 19394332
AN - SCOPUS:67650954364
SN - 0016-5085
VL - 137
SP - 639-648.e9
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -
