Open AccessInduction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma
Author(s) -
Hirshoren Nir,
Bulvik Raanan,
Neuman Tzahi,
Rubinstein Ariel M.,
Meirovitz Amichay,
Elkin Michael
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12179
Subject(s) - heparanase , head and neck squamous cell carcinoma , cancer research , heparan sulfate , extracellular matrix , oncogene , cancer , extracellular , biology , head and neck cancer , cell , chemistry , immunology , medicine , microbiology and biotechnology , biochemistry , cell cycle
High‐risk human papillomavirus ( HPV )‐positive head and neck squamous cell carcinomas ( HNSCC s) 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 HNSCC s. 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 HPV 16 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).