Regulation of angiogenesis by PEDF, anti-angiogenic factor, for controlling Oral Diseases

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The objectives in this study are to regulate oral cancer and to establish the method for repair in oral function by controlling angiogenesis. In this research, we examined the regulation mechanism for PEDF production and the molecular mechanism for anti-angiogenic activity of PEDF. When the human oral squamous cell carcinoma cell lines were exposed by ischemia, PEDF production was up-regulated, in contrast, PEDF was down-regulated by ischemia in normal cells. In ischemia, VEGF was up-regulated and this VEGF stimulated PEDF production via PEDFR-1. It is interesting that PEDF/VEGF ratio increased in benign tumor, but decreased dramatically in cancer. These results suggest that in cancer the low PEDF/VEGF ratio causes to angiogenesis in cancer tissue, and the part of angiogenesis is escaped from ischemia, which leads to decrease PEDF production. Next, we investigated here the possibility the involvement of the motif for ECM interaction in anti-angiogenic activity of PEDF. The growth rates of HeLa cells in culture were not affected by transfection of PEDF, indicating that PEDF did not suppress tumor cell growth directly. In tumor xenografts, overexpression of wild-type PEDF significantly suppressed tumor growth, whereas the mutant of collagen I-binding site of PEDF (Col-mut PEDF) did not inhibit tumor growth. The mutant of heparin-binding site of PEDF (Hep-mut PEDF) suppressed tumor growth. Histological analysis showed that the density and area of microvasculatures in either PEDF or Hep-mut PEDF were suppressed as compared with those in either vector or Col-mut PEDF. Our data indicate that PEDF inhibits tumor growth via anti-angiogenic activity, and the collagen I -binding motif of PEDF is involved in the biological activity. We also examined the cloning of PEDF receptor using by expression cloning technique. We got several genes to bind for PEDF, and we have examined whether these proteins was a receptor for PEDF.