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Analysis of institutional authors

Peso Ovalle, LuisAuthorOrtiz De Landazuri Busca, ManuelAuthorAragones, JAuthor

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February 12, 2014
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Specific oncolytic effect of a new hypoxia-inducible factor-dependent replicative adenovirus on von Hippel-Lindau-Defective renal cell carcinomas

Publicated to:CANCER RESEARCH. 63 (20): 6877-6884 - 2003-10-15 63(20), DOI:

Authors: Cuevas, Y; Hernández-Alcoceba, R; Aragones, J; Naranjo-Suárez, S; Castellanos, MC; Esteban, MA; Martín-Puig, S; Landazuri, MO; del Peso, L

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Abstract

Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for a hereditary cancer syndrome characterized by high susceptibility to hemangioblastomas of the retina and central nervous system, pheochromocytomas, and renal cell carcinomas. In agreement with its role as a tumor suppressor, the vast majority of spontaneous clear cell carcinomas of the kidney present loss of heterozygosity at the VHL locus. Recently, it has been shown that VHL works as the substrate recognition component of an E3 ubiquitination complex that targets the hypoxia-inducible factor (HIF) for proteosomal degradation. Under normal oxygen tension, the half-life of HIF transcription factors is extremely short because of its high degradation rate by the proteasome, resulting in undetectable HIF activity in normal cells. However, in VHL-deficient tumor cells, the HIF transcriptional pathway is constitutively activated because of impaired ubiquitination of this transcription factor. To target VHL-deficient tumors, we have exploited this feature to develop a conditionally replicative adenovirus (Ad9xHRE1A), the replication of which is HIF dependent. In this new oncolytic adenovirus, the expression of the E1A gene is controlled by an optimized minimal promoter containing HIF recognition elements. Here, we show that the induction of the E1A gene, as well as the viral replication and cytolytic effect of Ad9xHRE1A, are dependent on HIF activity. As a consequence, this virus efficiently kills VHL-deficient cells both in vitro and in vivo, as well as cells growing under hypoxic conditions. These data suggest that Ad9xHRE1A could be used as a highly specific therapy for VHL-deficient cancers and probably many other tumors that show extensive hypoxic areas or increased HIF activity by genetic alterations other than VHL loss.

Keywords

ActivationBreast-cancerExpressionInvolvementProtein

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal CANCER RESEARCH due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2003, it was in position 7/119, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-07-18:

  • Google Scholar: 57
  • WoS: 35
  • Scopus: 42
  • Europe PMC: 22

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Belgium; Birmingham.