Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma

Nir Hirshoren, Raanan Bulvik, Tzahi Neuman, Ariel M. Rubinstein, Amichay Meirovitz, Michael Elkin

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


High-risk human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCCs) are highly invasive; however the identity of downstream effectors responsible for their aggressive phenotype remains underinvestigated. Here, we report that HPV-mediated up-regulation of heparanase enzyme can provide mechanistic explanation for augmented invasiveness of HPV-positive HNSCCs. Heparanase is the sole mammalian enzyme (endo-β-d-glucuronidase) degrading heparan sulphate glycosaminoglycan, key polysaccharide of the extracellular matrix. Cleavage of heparan sulphate by heparanase leads to disassembly of extracellular barriers, enabling local invasion and metastatic spread of the tumour, and releases heparan sulphate-bound growth factors from the extracellular depots. Heparanase is tightly implicated in head and neck cancer progression; yet, molecular mechanisms underlying transcriptional activation of the heparanase gene in HNSCC are largely unknown. We found that HPV16 oncogene E6 is capable of inducing overexpression of heparanase in HNSCC. Notably, radiation treatment dose-dependently suppresses E6-induced heparanase expression in vitro. Our results provide the first evidence for a functional involvement of HPV in heparanase induction in head and neck tumourigenesis and, given ongoing clinical testing of several heparanase-inhibiting compounds, offer important avenue for future therapeutic exploration in HNSCC, as well as other HPV-associated malignancies (i.e. cervical carcinoma).

Original languageEnglish
Pages (from-to)181-186
Number of pages6
JournalJournal of Cellular and Molecular Medicine
Issue number1
StatePublished - 1 Jan 2014
Externally publishedYes


  • Head and neck cancer
  • Heparanase
  • Human papillomavirus

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology


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