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Nichtautonome Effekte des Onkogens YAP in der Hepatokarzinogenese

Nonautonomous effects of oncogenic YAP in hepatocarcinogenesis

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Zusammenfassung

Hintergrund

Der transkriptionelle Koaktivator „yes-associated protein“ (YAP) ist ein starkes Onkogen in der Hepatokarzinogenese.

Ziel der Arbeit

Ziel der Arbeit war es zu untersuchen, ob und wie YAP die Expression parakrin wirkender Faktoren in Hepatozyten und Leberkrebszellen beeinflusst.

Material und Methoden

Transkriptom- und Proteomanalysen muriner wildtypischer und YAP-transgener Hepatozyten zur Identifikation parakrin wirkender Proteine wurden durchgeführt. Mittels molekularer und biochemischer Methoden wurden die Mechanismen der YAP-abhängigen Regulation sezernierter Faktoren in humanen Leberkrebszelllinien untersucht. Die Expression von YAP-Zielgenen wurde mithilfe von Genexpressionsdaten von HCC(Leberzellkarzinom)-Patienten bestätigt.

Ergebnisse

Zahlreiche YAP-abhängige, sezernierte Faktoren (z. B. CXCL10, GDF15, PDGFB) konnten identifiziert werden. YAP reguliert zusammen mit Transkriptionsfaktoren der TEAD(„TEA domain“)-Proteinfamilie deren Expression. Die Dysregulation der sezernierten YAP-Zielgene korreliert in vielen Fällen mit einem schlechteren Überleben von Leberkrebspatienten.

Diskussion

YAP induziert parakrin wirkende Faktoren, welche direkt Einfluss auf das Tumormilieu nehmen können und somit potenziell die Tumorgenese beeinflussen. Gleichzeitig stellen diese multizellulären Netzwerke vielversprechende Zielstrukturen für neue therapeutische Ansätze dar.

Abstract

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.

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Förderung

S. Marquard und K. Breuhahn werden durch die Deutsche Krebshilfe gefördert.

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Authors and Affiliations

  1. Pathologisches Institut Heidelberg, Universität Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Deutschland

    S. Marquard, S. Thomann, S. M. E. Weiler, P. Schirmacher & K. Breuhahn

  2. Medizinische Fakultät Mannheim, Medical Research Center, Universität Heidelberg, Mannheim, Deutschland

    C. Sticht & N. Gretz

Authors
  1. S. Marquard
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  2. S. Thomann
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  3. S. M. E. Weiler
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  4. C. Sticht
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  5. N. Gretz
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  6. P. Schirmacher
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Correspondence to S. Marquard.

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Interessenkonflikt

S. Marquard, S. Thomann, S.M.E. Weiler, C. Sticht, N. Gretz, P. Schirmacher und K. Breuhahn geben an, dass kein Interessenkonflikt besteht.

Alle beschriebenen Untersuchungen wurden mit Zustimmung der zuständigen Ethikkommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt.

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Marquard, S., Thomann, S., Weiler, S.M.E. et al. Nichtautonome Effekte des Onkogens YAP in der Hepatokarzinogenese. Pathologe 38 (Suppl 2), 175–179 (2017). https://doi.org/10.1007/s00292-017-0361-2

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  • DOI: https://doi.org/10.1007/s00292-017-0361-2

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