title: Role of hypoxia-inducible transcription factor 1alpha for progression and chemosensitivity of murine hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is a hypervascularized tumor entity with association of arterial vessel density with poor prognosis. The hypoxia-inducible transcription factor HIF-1alpha represents a pivotal regulator of angiogenesis and is thought to determine the angiogenic nature of HCC. However, the precise role of HIF-1alpha during the pathogenesis of HCC remains elusive. We established a functional inactivation of HIF-1alpha in vitro and in vivo via RNAi and Cre/loxP-mediated recombination, respectively, to determine HIF-1alpha's role for tumor growth and chemosensitivity in transgenic and orthotopic murine HCC models. HIF-1alpha-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-1alpha-deficient tumors in the orthotopic and the transgenic HCC model, respectively. In line with the in vitro data, treatment of HIF-1alpha-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-1alpha for tumor growth and angiogenesis in two murine HCC models. However, our data point toward a significant function of HIF-1alpha in determining chemosensitivity of HCC and therefore warrant validation of HIF-1alpha-inhibitors as adjuvant therapeutic agents in clinical studies of human HCC.
authors.affiliation: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Katjana
authors.initials: K
authors.lastname: Daskalow
authors.forename: Nadine
authors.initials: N
authors.lastname: Rohwer
authors.forename: Esther
authors.initials: E
authors.lastname: Raskopf
authors.forename: Evelyne
authors.initials: E
authors.lastname: Dupuy
authors.forename: Anja
authors.initials: A
authors.lastname: Kühl
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Thorsten
authors.initials: T
authors.lastname: Cramer
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
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