Prospero -related homeobox 1 ( PROX1 ) is frequently inactivated by genomic deletions and epigenetic silencing in carcinomas of the bilary system

Background/Aims Functional deletion of the transcription factor Prospero -related homeobox 1 ( PROX1 ) causes abnormal cellular proliferation via down-regulated expression of the cell cycle inhibitors p27kip1 and p57kip2 . Hence, we examined whether inactivation of the PROX1 gene can be demonstrated...

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Published in:	Journal of hepatology Vol. 46; no. 1; pp. 89 - 97
Main Authors:	Laerm, Antonia, Helmbold, Peter, Goldberg, Martina, Dammann, Reinhard, Holzhausen, Hans-Jürgen, Ballhausen, Wolfgang Gerhard
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier B.V 01-01-2007 Elsevier
Subjects:	Aged Aged, 80 and over Base Sequence Biliary Tract Neoplasms - genetics Biliary Tract Neoplasms - metabolism Biliary Tract Neoplasms - pathology Biological and medical sciences Cholangiocarcinoma Chromosomes, Human, Pair 1 - genetics DNA Methylation DNA, Neoplasm - genetics Epigenesis, Genetic Female Gastroenterology and Hepatology Gastroenterology. Liver. Pancreas. Abdomen Gene Deletion Gene Silencing Genes, Homeobox Genes, Tumor Suppressor Homeodomain Proteins - antagonists & inhibitors Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Liver. Biliary tract. Portal circulation. Exocrine pancreas Loss of Heterozygosity Male Medical sciences Microsatellite Instability Middle Aged Promoter methylation Prospero-related homeobox 1 PROX1 Tumor suppressor Tumor Suppressor Proteins Tumors Promoter methylation Loss-of-heterozygosity PROX1 Tumor suppressor Cholangiocarcinoma Prospero-related homeobox 1 Immunohistochemistry Biliary tract Carcinoma Prospero-related homeobox 1; Tumor suppressor Hepatic disease Malignant tumor Biliary tract disease Heterozygosity Promoter Polymerase chain reaction Anatomic pathology Malignant cholangioma Gastroenterology Deletion Digestive diseases Suppressor Molecular biology Methylation Cholangiocarcinoma; Loss-of-heterozygosity; Promoter methylation; PROX1
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Summary:	Background/Aims Functional deletion of the transcription factor Prospero -related homeobox 1 ( PROX1 ) causes abnormal cellular proliferation via down-regulated expression of the cell cycle inhibitors p27kip1 and p57kip2 . Hence, we examined whether inactivation of the PROX1 gene can be demonstrated in malignant tumors of the bilary system. Methods Seventeen paraffin-embedded specimens of carcinomas of the bilary system were subjected to loss-of-heterozygosity (LOH) and microsatellite instability analyses, methylation-specific polymerase-chain reaction (MSP) and immunohistochemical detection of PROX1 protein in tumor sections. Results The marker D1S213 located close to PROX1 at 1q41 indicated LOH events in 50% of informative tumor samples analyzed. In contrast to intense cytoplasmic and nuclear staining of normal bile duct epithelia, PROX1 protein was absent or drastically reduced in 10 of 16 (63%) carcinomas. MSP revealed significant PROX1 promoter hypermethylation in 8 out of 17 clinical cases (47%). A correlation between clinicopathological characteristics and reduced PROX1 expression was not observed. Conclusions We demonstrate that mechanisms like genomic deletions and hypermethylation, which are prototypic for the inactivation of tumor suppressor genes, inactivate PROX1 in carcinomas of the bilary system. Our findings prompt the elucidation of molecular pathways involved in PROX1 dependent misregulation of differentiation and proliferation processes in bilary tract carcinomas.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0168-8278 1600-0641
DOI:	10.1016/j.jhep.2006.07.033