Wnt-signaling and glutamine synthetase expression in human hepatocellular carcinomas

The liver specific expression of enzymes under normal conditions and in pathological situations is still enigmatic. Recently, the phenomenon of differential expression of enzymes along the porto-central axis of the liver acinus was demonstrated to be dependent on signal transduction pathways that are also important for the development of hepatocellular carcinoma (HCC). Most attention was drawn on the wnt-signaling pathway and its components beta-catenin and APC. Interestingly, the most prominent example of zonated expression in the normal liver –that of glutamine synthetase (GS) around the central veins- was shown to be regulated by wnt-signaling. We now provide evidence that the expression of GS in human HCC is in fact also highly associated with active wnt-signaling as exemplified by the nuclear/cytoplasmic presence of beta-catenin. In addition, we identified a cis-regulatory element within the GS gene that is responsible for reporter gene activation in the presence of activating beta-catenin mutations found in the HCCs analysed. However, our experiments demonstrate that the activation of endogenous GS is not the result of a simple interaction between a cis-regulatory element and a transcription factor complex activated by the nuclear presence of beta-catenin. Together, our recent data sheds new light on the role of liver specific gene expression under the control of wnt-signaling in the normal and pathologic situation.

Literatur: Max Werth, Rolf Gebhardt and Frank Gaunitz (2006) Hepatic expression of glutamine synthetase in rats is controlled by STAT5 and TCF transcription factors. Hepatology, in press.

STAT5 - Wnt - beta-catenin - glutamine synthetase