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Leberspezifische Transkriptionsfaktoren und deren Bedeutung in kolorektalen Lebermetastasen

Regulation of liver-enriched transcription factors in colorectal liver metastases
: Lehner, F.; Klempnauer, J.; Borlak, J.


Steinau, H.-U. ; Deutsche Gesellschaft für Chirurgie:
Chirurgisches Forum 2007 für experimentelle und klinische Forschung : 124. Kongress der Deutschen Gesellschaft für Chirurgie München, 01.05.-04.05.2007
Berlin: Springer, 2007 (Deutsche Gesellschaft für Chirurgie. Forumband 36)
ISBN: 978-3-540-71122-3
ISBN: 3-540-71122-8
Deutsche Gesellschaft für Chirurgie (Kongress) <124, 2007, München>
Fraunhofer ITEM ()
HNF6; Foxa2; liver - tumor; transcription factor; metastasis; colonic tumor

Background and Aims:
The molecular causes leading to secondary liver malignancies are unknown. We therefore investigated regulation of major hepatic nuclear factors in primary human colonic cancer and colorectal liver metastases.
Expression of liver enriched transcription factors was studied by reverse-transcription polymerase chain reaction, by gene chip analysis and Western blotting technique.
DNA binding of liver enriched transcription factors was studied by electromobility shift assay (EMSA) an genomic sequencing of HNF&.
Many of the liver enriched transcription factors were expressed in primary tumours of the colon an in colorectal liver metastases, but HFN6 gene and protein expression was confined to liver metastatic growth.
Though abundantly expressed, HNF6 was unable to bind to promotor sequences of targeted genes.
Genomic sequencing did not indicate variations in the binding domains of HNF6, but Western blotting of HNF6 identified unacetylated HNF6 as a hallmark of colorectal liver metastases.
Because of its known interaction with HNF6 expression of Foxa2 was investigated and found to be specifically induced in colorectal liver metastases.
Furthermore, expression of genes targeted by HNF6 was studied by gene chip analysis and found to be mostly repressed except for tumour growth.
HNF6 protein expression in colorectal liver metastases is driven by the hepatic environment. It is not expressed in healthy or primary colonic cancer.
DNA binding of HNF6 is selctively abrogated through lack of posttranslational modification and interaction with Foxa2. Targeting HNF6 may enable mechanism based therapy for colorectal liver metastases by reversing the malignant phenotype.