Z Gastroenterol 2019; 57(01): e68
DOI: 10.1055/s-0038-1677227
4. Tumors
Georg Thieme Verlag KG Stuttgart · New York

PRRX1 cooperate with ZEB1/ZEB2 in hepatocellular carcinoma

W Pioronska
1   Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, University of Heidelberg, Germany
,
ZC Nwosu
1   Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, University of Heidelberg, Germany
,
MP Ebert
1   Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, University of Heidelberg, Germany
,
S Dooley
1   Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, University of Heidelberg, Germany
,
C Meyer
1   Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, University of Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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    Background & aims:

    Hepatocellular carcinoma (HCC) is the most common liver cancer with poor prognosis. Paired related homeobox 1 (PRRX1) is a transcriptional co-activator, which regulates cell growth and differentiation. PRRX1 was linked to epithelial to mesenchymal transition (EMT). To date, it is unknown whether PRRX1 has a functional relevance in HCC. We performed an in-depth analysis of PRRX1 expression, its co-expressed genes and functions in HCC.

    Methods:

    The expression of PRRX1 in human HCC was assessed in online databases as well as in microarray datasets encompassing > 1,200 liver tumour profiles. We applied a bioinformatics approach to analyze functional annotation of genes correlated with PRRX1 in HCC, followed by Kaplan-Meier overall survival analysis. In vitro, PRRX1 expression was analyzed in HCC cell lines. Further, PRRX1 and zinc finger E-box-binding homeobox 1/2 (ZEB1/ZEB2) expression was modulated by siRNA. Cells were then treated with transforming growth factor β (TGF-β), followed by functional assays on proliferation and clonogenicity.

    Results:

    PRRX1 is frequently upregulated in human HCC. Pathway annotation analysis identified extracellular matrix activities, Akt signaling, focal adhesion and metabolism as processes strongly associated with PRRX1 in clinical tissues. We have identified the two EMT related transcription factors, ZEB1 and ZEB2, as novel PRRX1-related genes in HCC. PRRX1 expression per se did not predict overall survival. However, PRRX1 in combination with ZEBs significantly predicted survival outcome in HCC. In cell lines, PRRX1 expression was variable, being higher in cells that display epithelial morphology. Consistent with the positive correlation with ZEBs, knockdown of PRRX1 led to downregulation of ZEBs. Moreover, TGF-β modulates PRRX1 and ZEBs expression. Intriguingly, knockdown of PRRX1 as well as ZEB2 led to higher proliferation and clonogenicity in HCC.

    Conclusion:

    We identify ZEB1/ZEB2 as transcriptional regulators that may act in concert with PRRX1 to influence tumour characteristics.


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