Altered regulation of Prox1-gene-expression in liver tumors.
BACKGROUND
Prospero-related homeobox 1 (Prox1) transcription factor was described as a tumor-suppressor gene in liver tumors. In contrast, Prox1 knock out in murine embryos drastically reduces proliferation of hepatoblasts.


METHODS
We have studied the expression of Prox1 in normal liver, liver cirrhosis and peritumoral liver samples in comparison to hepatocellular (HCC) and cholangiocellular carcinoma (CCC) at mRNA, protein and functional levels.


RESULTS
Prox1 was found in hepatocytes of normal liver, while normal bile duct epithelial cells were negative. However, Prox1+ cells, which co-expressed biliary epithelial makers and showed ductular morphology, could be detected within fibrotic septa of cirrhotic livers, and in both HCC and CCC. Two Prox1 mRNA isoforms (2.9 kb and 7.9 kb) were identified with a prevalence of the longer isoform in several HCC samples and the shorter in most CCC samples. Evidence was provided that Myc-associated zinc finger protein (MAZ) might significantly contribute to the gene expression of Prox1 in HCC, while neo-expression of Prox1 in CCC remains to be resolved. A point mutation in the prospero domain of Prox1 was found in one HCC sample.


CONCLUSIONS
Our study shows dysregulation of Prox1 in liver cirrhosis, HCC and CCC, such as neo-expression in cells with biliary epithelial phenotype in liver cirrhosis, and in CCC. Altered Prox1 mRNA expression is partly regulated by MAZ, and mutation of the prospero domain in HCC indicates an involvement for Prox1 during tumor progression.
Dudas
Jozsef
J
Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Georg-August-University Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. jdudas@gwdg.de <jdudas@gwdg.de>
Mansuroglu
Tümen
T
Moriconi
Federico
F
Haller
Florian
F
Wilting
Joerg
J
Lorf
Thomas
T
Füzesi
Laszlo
L
Ramadori
Giuliano
G
D000230:Adenocarcinoma / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000235:genetics; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein