Die Rolle von CUX1 bei Hypoxie von hepatischen Sternzellen

Liver fibrosis is the most common end stage of chronic liver diseases. This work contributes to a better understanding of the function of CUX1 in hepatic stellate cells and its involvement in the pathogenesis of liver fibrosis. CUX1 is a transcription factor that belongs to the homeobox proteins. It is responsible for the transcription of genes that control a variety of processes. It can contribute to carcinogenesis, including hepatocellular carcinoma (HCC). In renal cell carcinoma CUX1 suppresses the factor inhibiting HIF-1 (FIH-1) and leads to increased level of the hypoxia marker HIF-1. This work focuses on the role of CUX1 in hepatic stellate cells under hypoxic stress and investigates whether its suppression leads to a change in the physiological process. The established cobalt chloride model and the hypoxia chamber were used as hypoxia models. A knockdown is achieved by transfection with siRNA against CUX1. The expression of hypoxia markers, activation markers and cell cycle markers was performed by qRT-PCR and by Western blot. The relationship between CUX1 and HIF-1 was further investigated by transfection with a plasmid containing a promoter sequence for HIF1A and simultaneous CUX1- suppression. The results illustrate that CUX1 controls the activation of hepatic stellate cells under hypoxia. As a repressor of COL1A1, the gene encoding for collagen type 1, a CUX1-knockdown can contribute to an increased formation of the extracellular matrix. Furthermore, an indirect influence on the adaptation of cells to hypoxia by repression of the factor inhibiting HIF-1 (FIH-1) was observed, thus supporting the previous findings observed in renal cell carcinoma. CUX1-suppression promotes the hypoxic response of hepatic stellate cells. Although, a direct relationship between CUX1 and HIF-1 could not be demonstrated. In addition CUX1-downregulation leads to an increase of CDKN1A-transcription. CUX1 is physiologically relevant in the homeostasis of stellate cell dormancy. Changes in CUX1-expression or function may contribute to pathomechanisms in the liver and should be the subject of future research.