Journal of Molecular Medicine

, Volume 88, Issue 8, pp 817–827 | Cite as

Role of hypoxia-inducible transcription factor 1α for progression and chemosensitivity of murine hepatocellular carcinoma

  • Katjana Daskalow
  • Nadine Rohwer
  • Esther Raskopf
  • Evelyne Dupuy
  • Anja Kühl
  • Christoph Loddenkemper
  • Bertram Wiedenmann
  • Volker Schmitz
  • Thorsten CramerEmail author
Original article


Hepatocellular carcinoma (HCC) is a hypervascularized tumor entity with association of arterial vessel density with poor prognosis. The hypoxia-inducible transcription factor HIF-1α represents a pivotal regulator of angiogenesis and is thought to determine the angiogenic nature of HCC. However, the precise role of HIF-1α during the pathogenesis of HCC remains elusive. We established a functional inactivation of HIF-1α in vitro and in vivo via RNAi and Cre/loxP-mediated recombination, respectively, to determine HIF-1α’s role for tumor growth and chemosensitivity in transgenic and orthotopic murine HCC models. HIF-1α-deficient HCC cells displayed significantly reduced anchorage-independent growth and enhanced sensitivity toward etoposide, while basic cellular proliferation was unaffected. Analysis of gross tumor growth failed to detect reduced growth of HIF-1α-deficient tumors in the orthotopic and the transgenic HCC model, respectively. In line with the in vitro data, treatment of HIF-1α-deficient tumors with etoposide resulted in greater antiproliferative efficacy when compared to wild-type mice. Taken together, our study does not support a pivotal role of HIF-1α for tumor growth and angiogenesis in two murine HCC models. However, our data point toward a significant function of HIF-1α in determining chemosensitivity of HCC and therefore warrant validation of HIF-1α-inhibitors as adjuvant therapeutic agents in clinical studies of human HCC.


Hypoxia HIF-1α HCC Chemotherapy 



This work was supported by grants from the Deutsche Forschungsgemeinschaft (Cr 133/2-1, 133/2-2 and 133/2-3) and the Berliner Krebsgesellschaft (CRFF200804) to TC. NR was supported by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 276/4 - "Signalerkennung und -umsetzung").

Disclosure of potential conflict of interests

The authors declare no conflict of interests related to this study.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Katjana Daskalow
    • 1
  • Nadine Rohwer
    • 1
  • Esther Raskopf
    • 2
  • Evelyne Dupuy
    • 3
  • Anja Kühl
    • 4
  • Christoph Loddenkemper
    • 4
  • Bertram Wiedenmann
    • 1
  • Volker Schmitz
    • 2
  • Thorsten Cramer
    • 1
    • 5
    Email author
  1. 1.Medizinische Klinik mit Schwerpunkt Hepatologie und GastroenterologieCharité-Universitätsmedizin Berlin, Campus Virchow-KlinikumBerlinGermany
  2. 2.Medizinische Klinik und Poliklinik IUniversitätsklinikum BonnBonnGermany
  3. 3.Institut des Vaisseaux et du SangUniversité Paris 7-Denis Diderot, Hôpital LariboisièreParisFrance
  4. 4.Institut für PathologieCharité-Universitätsmedizin Berlin, Campus Benjamin FranklinBerlinGermany
  5. 5.Molekulares KrebsforschungszentrumCharité-Universitätsmedizin BerlinBerlinGermany

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