ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.
OBJECTIVE
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.
Herbst
Andreas
A
Department of Medicine II, University of Munich, Munich, Germany.
Bommer
Guido T
GT
Kriegl
Lydia
L
Jung
Andreas
A
Behrens
Andrea
A
Csanadi
Endy
E
Gerhard
Markus
M
Bolz
Christian
C
Riesenberg
Rainer
R
Zimmermann
Wolfgang
W
Dietmaier
Wolfgang
W
Wolf
Isabella
I
Brabletz
Thomas
T
Göke
Burkhard
B
Kolligs
Frank T
FT
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000073940:Transcription Factor 4; D014157:Transcription Factors; C407909:TCF3 protein, human; C532096:TCF4 protein, human