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Background: The transcriptional coactivator yes-associated protein (YAP) is a strong oncogene in liver cancer development., Objectives: To investigate if and how YAP-induced paracrine-acting factors are regulated in hepatocytes and liver cancer cells., Material and Methods: Transcriptome analysis and proteomics of murine wildtype and YAP-transgenic hepatocytes were performed to identify paracrine-acting proteins. Molecular and biochemical techniques were used to examine the mechanisms of YAP-dependent gene regulation. Gene expression data from HCC (hepatocellular carcinoma) patients was evaluated., Results: Several YAP-dependent, secreted factors (e. g. CXCL10, GDF15, PDGFB) were identified. YAP regulates these factors through transcription factors of the TEAD (TEA domain) protein family. Moreover, the dysregulation of the YAP-target genes is often associated with poor HCC patient prognosis., Conclusions: YAP induces the expression of paracrine-acting factors that may affect the tumor microenvironment and therefore support carcinogenesis. This multicellular network could allow the development of novel and specific perturbation approaches.

In the development of a tumour a multistep process is existing, in which after activation of a cellular oncogen and after efficacy of a viral oncogenat first an avalanche-like increase of transforming, excluding the regulation of cell division proteins takes place. In many forms of tumours the transforming proteins possess the property of protein kinases and phosphorylize proteins situated in the area of the cell membrane. In some forms of tumours an enrichment in the area of the cell nucleus takes place. Secondarily, in the tumour cells frequently other oncogens are activated and an activation of further genes for the formation of growth factors or of proteins of the histocompatibility complex, respectively, occurs. Some transforming proteins themselves possess the properties of growth factors and of receptors, respectively, for the binding of such ones. Cocarcinogens activate the protein kinase C, e.g. the phorbol esters. Anticarcinogens influence the transcription, e.g. the vitamin A and the 1,25-dihydroxyvitamin D3. Vitamin A and analogous compounds increases the functional capacity of the immune defense.