title: Heparanase induces signal transducer and activator of transcription (STAT) protein phosphorylation: preclinical and clinical significance in head and neck cancer.
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).
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cohen-Kaplan
authors.forename: Jenny
authors.initials: J
authors.lastname: Jrbashyan
authors.forename: Yoav
authors.initials: Y
authors.lastname: Yanir
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.forename: Ofer
authors.initials: O
authors.lastname: Ben-Izhak
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Ilana
authors.initials: I
authors.lastname: Doweck
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005966:Glucuronidase / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D009669:Nose Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
chemical_list: D066246:ErbB Receptors; D005966:Glucuronidase; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D000099175:Heparanase; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494092:STAT5A protein, human; C494095:STAT5B protein, human