Growth regulation mediated by EGF family of growth factors

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HB-EGF is a member of the EGF family growth factors. This factor is synthesized as proHB-EGF, a membrane-anchored precursor protein, and is cleaved on the cell surface to yield the soluble growth factor. The conversion of proHB-EGF into the soluble form is critical for the activity of this growth factor, and therefore this process is tightly regulated. We found that, among the EGFR family of growth factors, HB-EGF gene expression in cancerous tissues of ovarian cancer 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 proHB-EGF, and completely blocked by proHB-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. 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.