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