Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy.
Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Shingo
S
Miyamoto
Michinari
M
Hirata
Ayano
A
Yamazaki
Takuya
T
Kageyama
Hidetoshi
H
Hasuwa
Hiroto
H
Mizushima
Yoshihiro
Y
Tanaka
Hiroshi
H
Yagi
Kenzo
K
Sonoda
Masahiro
M
Kai
Hideo
H
Kanoh
Hitoo
H
Nakano
Eisuke
E
Mekada
D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D011956:Receptors, Cell Surface / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D001426:Bacterial Proteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D011956:Receptors, Cell Surface; C028581:CRM197 (non-toxic variant of diphtheria toxin); D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C032881:lysophosphatidic acid