Abstract
BackgroundProspero-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.MethodsWe 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.ResultsProx1 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.ConclusionOur 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.
Highlights
Prospero-related homeobox 1 (Prox1) transcription factor was described as a tumor-suppressor gene in liver tumors
Altered Prox1 mRNA expression is partly regulated by Myc-associated zinc finger protein (MAZ), and mutation of the prospero domain in HCC indicates an involvement for Prox1 during tumor progression
In some HCC cases the Prox1 mRNA expression was higher compared to the average of the normal liver, which in one case was related with mutation
Summary
Prospero-related homeobox 1 (Prox1) transcription factor was described as a tumor-suppressor gene in liver tumors. Homeobox genes encode transcription factors that control cell differentiation and play essential roles during embryonic development [1,2]. The homeobox genes Hlx [3], Hex [4] and the prospero-related homeobox 1 (Prox1) [5] are involved in the development of the liver bud. In our previous study it was shown that Prox remains a stabile marker of hepatocytes in normal adult, injured and regenerating liver, whereas it is not detectable in biliary epithelial cells [10]. Prox was found to regulate metabolic function in hepatocytes, and to be involved in the regulation of other transcription factors [11]
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