Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy

Shingo Miyamoto, Michinari Hirata, Ayano Yamazaki, Takuya Kageyama, Hidetoshi Hasuwa, Hiroto Mizushima, Yoshihiro Tanaka, Hiroshi Yagi, Kenzo Sonoda, Masahiro Kai, Hideo Kanoh, Hitoo Nakano, Eisuke Mekada

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Abstract

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.

Original languageEnglish
Pages (from-to)5720-5727
Number of pages8
JournalCancer Research
Volume64
Issue number16
DOIs
Publication statusPublished - 2004 Aug 15
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Miyamoto, S., Hirata, M., Yamazaki, A., Kageyama, T., Hasuwa, H., Mizushima, H., Tanaka, Y., Yagi, H., Sonoda, K., Kai, M., Kanoh, H., Nakano, H., & Mekada, E. (2004). Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Cancer Research, 64(16), 5720-5727. https://doi.org/10.1158/0008-5472.CAN-04-0811