PT  - JOURNAL ARTICLE
AU  - Miyamoto, Shingo
AU  - Tanaka, Yoshihiro
AU  - Yagi, Hiroshi
AU  - Sonoda, Kenzo
AU  - Nakano, Hitoo
AU  - Mekada, Eisuke
TI  - HB-EGF is a targeting molecule for the treatment of ovarian cancer
DP  - 2004 Apr 01
TA  - Cancer Research
PG  - 1198--1198
VI  - 64
IP  - 7 Supplement
4099  - http://cancerres.aacrjournals.org/content/64/7_Supplement/1198.2.short
4100  - http://cancerres.aacrjournals.org/content/64/7_Supplement/1198.2.full
SO  - Cancer Res2004 Apr 01; 64
AB  - Proc Amer Assoc Cancer Res, Volume 45, 2004 5196 Purpose: Impaired EGF system and elevated LPA has been implicated in the acceleration of tumor growth in ovarian cancer. HB-EGF can trans-regulate LPA and EGFR signal. To demonstrate that HB-EGF regulates tumorigenic properties in ovarian cancer, we examined the activation of EGFR and MAPK, and tumorigenicity on nude mice using SKOV-3 and the stable transfected cells with wild or chimeric HB-EGF cDNA. Methods: The human wild type (HB), the mutated type (MHB) which cannot be cleaved, the soluble form (SHB) of HB-EGF cDNA , and siRNA for HB-EGF (181) were constructed into the vectors Resulting plasmids were transfected into SKOV-3 cells and then the stable cell lines were established. In these stable cell lines, HB-EGF expression on cells and the activation of EGFR and MAPK were examined in binding assay using 125I labeled diphtheria toxin and western blotting, respectively. The size of tumor on nude mice were measured at every week after the inoculation of these cells. A specific inhibitor, CRM197 for HB-EGF, suramine (LPA antagonist), GM6001 (protease inhibitor), 153035 (EGFR inhibitor), and 98056 (MEK inhibitor), were used for these cells to evaluate the relationship between LPA and EGFR signal. Results: Each cpm gamma-count in SKOV-3, HB, MHB, SHB, 181 cells was approximate 3000, 22000, 25000, 2200, and 900 cpm. HB and SHB cells had high activation of EGFR and MAPK and marked increase of tumor growth, compared to SKOV-3. The activation of EGFR and MAPK and tumor growth were completely suppressed in MHB and 181 cells. These results indicated that the activation of EGFR and MAPK and an increase of tumor growth were dependent on the expression of proHB-EGF and that HB-EGF expression as an autocrine or paracrine, not juxtacrine action induced the activation of EGFR and MAPK and an increase of tumor growth. In SKOV-3 and HB cells, each block of LPA or EGFR signal induced the suppression of both the proteolytic cleavage of HB-EGF and the activation of EGFR and MAPK. These results indicated that LPA signal is involved in signal associated with HB-EGF . The administration of CRM197 attenuated the activation of EGFR and MAPK, and the increase of tumor growth. These results indicated that the inhibition of signal associated with HB-EGF lead to the treatment for ovarian cancer. Conclusion: HB-EGF is considered as a promising molecule to develop the targeting therapy for ovarian cancer.