Abstract
Activity of heparanase is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, heparanase enhances the phosphorylation of selected signaling molecules, including SRC and EGFR, in a manner that requires secretion but not enzymatic activity of heparanase and is mediated by its C-terminal domain. Clinically, heparanase staining is associated with larger tumors and increased EGFR phosphorylation in head and neck carcinoma. We hypothesized that signal transducer and activator of transcription (STAT) proteins mediate the protumorigenic function of heparanase downstream of the EGFR. We provide evidence that heparanase enhances the phosphorylation of STAT3 and STAT5b but not STAT5a. Moreover, enhanced proliferation of heparanase transfected cells was attenuated by STAT3 and STAT5b siRNA, but not STAT5a or STAT1 siRNA. Clinically, STAT3 phosphorylation was associated with head and neck cancer progression, EGFR phosphorylation, and heparanase expression and cellular localization. Notably, cytoplasmic rather than nuclear phospho-STAT3 correlated with increased tumor size (T-stage; p = 0.007), number of metastatic neck lymph nodes (p = 0.05), and reduced survival of patients (p = 0.04).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cells, Cultured
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Disease Progression
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ErbB Receptors / metabolism
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Female
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Fibroblasts / cytology
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Fibroblasts / enzymology
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Glucuronidase / metabolism*
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Head and Neck Neoplasms / metabolism*
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Head and Neck Neoplasms / pathology
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Humans
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Laryngeal Neoplasms / metabolism
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Laryngeal Neoplasms / pathology
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Male
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Mice
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Nose Neoplasms / metabolism
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Nose Neoplasms / pathology
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Phosphorylation / physiology
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism*
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Tongue Neoplasms / metabolism
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Tongue Neoplasms / pathology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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STAT5A protein, human
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STAT5B protein, human
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Tumor Suppressor Proteins
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ErbB Receptors
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heparanase
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Glucuronidase