| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
1 Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 2 Department of Cell Biology, Research Institute for Microbial Diseases and 3 Department of Experimental Genome Research, Genome Information Research Center, Osaka University, Osaka, Japan; and 4 Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan
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.
This article has been cited by other articles:
|
|
 |
|
  K. D. Cowden Dahl, J. Symowicz, Y. Ning, E. Gutierrez, D. A. Fishman, B. P. Adley, M. S. Stack, and L. G. Hudson Matrix Metalloproteinase 9 Is a Mediator of Epidermal Growth Factor-Dependent E-Cadherin Loss in Ovarian Carcinoma Cells Cancer Res., June 15, 2008; 68(12): 4606 - 4613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. McGowan, E. McKiernan, F. Bolster, B. M. Ryan, A. D. K. Hill, E. W. McDermott, D. Evoy, N. O'Higgins, J. Crown, and M. J. Duffy ADAM-17 predicts adverse outcome in patients with breast cancer Ann. Onc., June 1, 2008; 19(6): 1075 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Xie, H. Wang, S. Tranguch, R. Iwamoto, E. Mekada, F. J. DeMayo, J. P. Lydon, S. K. Das, and S. K. Dey Maternal heparin-binding-EGF deficiency limits pregnancy success in mice PNAS, November 13, 2007; 104(46): 18315 - 18320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Wang, C. Sloss, X. Zhang, S. W. Lee, and J. C. Cusack Membrane-Bound Heparin-Binding Epidermal Growth Factor Like Growth Factor Regulates E-Cadherin Expression in Pancreatic Carcinoma Cells Cancer Res., September 15, 2007; 67(18): 8486 - 8493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kageyama, M. Ohishi, S. Miyamoto, H. Mizushima, R. Iwamoto, and E. Mekada Diphtheria Toxin Mutant CRM197 Possesses Weak EF2-ADP-ribosyl Activity that Potentiates its Anti-tumorigenic Activity J. Biochem., July 1, 2007; 142(1): 95 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Said, I. Najwer, and K. Motamed Secreted Protein Acidic and Rich in Cysteine (SPARC) Inhibits Integrin-Mediated Adhesion and Growth Factor-Dependent Survival Signaling in Ovarian Cancer Am. J. Pathol., March 1, 2007; 170(3): 1054 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Snider and K. E. Meier Receptor transactivation cascades. Focus on "Effects of {alpha}1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells" Am J Physiol Cell Physiol, January 1, 2007; 292(1): C1 - C3. [Full Text] [PDF]
|
|
|
|
|
|
M. Kai, F. Sakane, Y.-J. Jia, S.-i. Imai, S. Yasuda, and H. Kanoh Lipid Phosphate Phosphatases 1 and 3 Are Localized in Distinct Lipid Rafts J. Biochem., November 1, 2006; 140(5): 677 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhao, D. He, B. Saatian, T. Watkins, E. Wm. Spannhake, N. J. Pyne, and V. Natarajan Regulation of Lysophosphatidic Acid-induced Epidermal Growth Factor Receptor Transactivation and Interleukin-8 Secretion in Human Bronchial Epithelial Cells by Protein Kinase C{delta}, Lyn Kinase, and Matrix Metalloproteinases J. Biol. Chem., July 14, 2006; 281(28): 19501 - 19511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Hills, V. M. Abrahams, B. Gonzalez-Timon, J. Francis, B. Cloke, L. Hinkson, R. Rai, G. Mor, L. Regan, M. Sullivan, et al. Heparin prevents programmed cell death in human trophoblast Mol. Hum. Reprod., April 1, 2006; 12(4): 237 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kioi, S. Takahashi, M. Kawakami, K. Kawakami, R. J. Kreitman, and R. K. Puri Expression and Targeting of Interleukin-4 Receptor for Primary and Advanced Ovarian Cancer Therapy Cancer Res., September 15, 2005; 65(18): 8388 - 8396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Braun and R. J. Coffey Lysophosphatidic Acid, a Disintegrin and Metalloprotease-17 and Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Ovarian Cancer: The First Word, Not the Last Clin. Cancer Res., July 1, 2005; 11(13): 4639 - 4643. [Full Text] [PDF]
|
|
|
|
|
|
Y. Tanaka, S. Miyamoto, S. O. Suzuki, E. Oki, H. Yagi, K. Sonoda, A. Yamazaki, H. Mizushima, Y. Maehara, E. Mekada, et al. Clinical Significance of Heparin-Binding Epidermal Growth Factor-Like Growth Factor and A Disintegrin and Metalloprotease 17 Expression in Human Ovarian Cancer Clin. Cancer Res., July 1, 2005; 11(13): 4783 - 4792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gutwein, A. Stoeck, S. Riedle, D. Gast, S. Runz, T. P. Condon, A. Marme, M.-C. Phong, O. Linderkamp, A. Skorokhod, et al. Cleavage of L1 in Exosomes and Apoptotic Membrane Vesicles Released from Ovarian Carcinoma Cells Clin. Cancer Res., April 1, 2005; 11(7): 2492 - 2501. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
