Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597476
4. Tumors/Liver Surgery
Georg Thieme Verlag KG Stuttgart · New York

Hypoxia causes down-regulation of Dicer in hepatocellular carcinoma, which is required for up-regulation of hypoxia inducible factor 1α and epithelial-mesenchymal transition

AA Ibrahim
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
C Schmithals
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
E Kowarz
3   Goethe-University of Frankfurt Biocenter, Institute of Pharmaceutical Biology, Frankfurt/Main, Germany
,
V Köberle
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
B Kakoschky
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
T Pleli
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
O Kollmar
4   HELIOS Dr. Horst Schmidt- Kliniken, Department of General and Visceral Surgery, Wiesbaden, Germany
,
S Nitsch
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
O Waidmann
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
F Finkelmeier
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
S Zeuzem
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
HW Korf
5   University Hospital Frankfurt, Institute of Anatomy 2, Frankfurt/Main, Germany
,
T Schmid
6   Goethe-University Frankfurt, Institute of Biochemistry I, Frankfurt/Main, Germany
,
A Weigert
6   Goethe-University Frankfurt, Institute of Biochemistry I, Frankfurt/Main, Germany
,
B Kronenberger
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
,
R Marschalek
3   Goethe-University of Frankfurt Biocenter, Institute of Pharmaceutical Biology, Frankfurt/Main, Germany
,
A Piiper
1   University Hospital Frankfurt, Department of Medicine 1, Frankfurt/Main, Germany
› Author Affiliations
Further Information
Piiper, Albrecht

Publication History

Publication Date:
19 December 2016 (online)

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    Purpose: A role of Dicer, which converts precursor miRNAs to mature miRNAs, in the tumor-promoting effect of hypoxia is currently emerging in some tumor entities. Its role in hepatocellular carcinoma (HCC) is unknown.

    Experimental design: HepG2 and Huh-7 cells were stably transfected with an inducible Dicer expression vector and were exposed to hypoxia/normoxia. HepG2-Dicer xenografts were established in nude mice; hypoxic areas and Dicer were detected in HCC xenografts and HCCs from mice with endogenous hepatocarcinogenesis; epithelial mesenchymal transition (EMT) markers were analyzed by immunohistochemistry or by immunoblotting. The correlation between Dicer and carbonic anhydrase 9 (CA9), a marker of hypoxia, was investigated in resected human HCCs.

    Results: Hypoxia increased EMT markers in vitro and in vivo and led to a downregulation of Dicer in HCC cells. The levels of Dicer were down-regulated in hypoxic tumor regions in mice with endogenous hepatocarcinogenesis and in HepG2 xenografts. In human HCCs the levels of Dicer correlated inversely with those of CA9, indicating that the negative regulation of Dicer by hypoxia also applies to HCC patients. Forced expression of Dicer prevented the hypoxia-induced increase in hypoxia inducible factor 1α (HIF-1α), hypoxia-inducible genes (CA9, glucose transporter 1), EMT markers and cell migration.

    Conclusions: We here identify down-modulation of Dicer as novel essential process in hypoxia-induced EMT in HCC and demonstrate that induced expression of Dicer counteracted hypoxia-induced EMT. Thus, targeting hypoxia-induced down-modulation of Dicer is a promising novel strategy to reduce HCC progression.


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    No conflict of interest has been declared by the author(s).

    Piiper, Albrecht