Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas.
We previously reported that schwannoma-derived growth factor (SDGF), a member of heparin-binding epidermal growth factor (EGF) family, participates in autocrine pathways and promotes rat glioma cell growth. To investigate the potential role of similar molecules in human gliomas, we examined 7 human glioma cell lines and 11 glioblastoma specimens for expression of the human homologue of SDGF, amphiregulin (AR), as well as heparin-binding EGF-like growth factor (HB-EGF). Northern blot analysis revealed that only one cell line and no tumor specimens expressed AR mRNA. In contrast, HB-EGF mRNA was expressed in all human glioma cell lines and its level of expression was two- to five-fold higher than that of control brain tissues in 8 of 11 glioblastoma cases. Immunohistochemistry demonstrated that membrane-anchored HB-EGF (proHB-EGF) and EGFR were co-expressed in 44% of 34 human malignant gliomas. Introduction of exogenous HB-EGF (10 ng/ml) increased human glioma cell proliferation, and anti-HB-EGF blocking antibodies reduced the growth of glioma cells by 30-40%, confirming the presence of an autocrine loop. When added to the medium, transforming growth factor-alpha, basic fibroblast growth factor, or HB-EGF rapidly induced HB-EGF mRNA expression. These results indicate that HB-EGF and proHB-EGF contribute to the growth of human malignant glioma cells, most likely through autocrine and juxtacrine mechanisms.
Mishima
K
K
Department of Neurosurgery, Faculty of Medicine, University of Tokyo, Japan.
Higashiyama
S
S
Asai
A
A
Yamaoka
K
K
Nagashima
Y
Y
Taniguchi
N
N
Kitanaka
C
C
Kirino
T
T
Kuchino
Y
Y
D066258:Amphiregulin; D002455:Cell Division / Q000187:drug effects; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008938:Mitosis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
C587848:AREG protein, human; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D066246:ErbB Receptors