ID1 signaling.

The Journal of biological chemistry 2010 Aug 2; In press

Qiu H, Yang B, Pei Z ZC, Zhang Z, Ding K

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China;

The highly expressed Id1 (inhibitor of DNA binding/differentiation) protein promotes angiogenesis in HCC and is a well-established target for anti-angiogenesis therapeutic strategies. Heparan sulphate (HS) mimetics such as PI-88 can abrogate HS-protein interactions to inhibit angiogenesis. Id1 is the direct downstream effector of BMPs (Bone morphogenetic proteins), which are angiogenic and HS binding proteins. Thus, targeting BMPs by HS mimetics may inhibit angiogenesis via attenuating Id1 expression. We report here that a HS mimetic WSS25 potently inhibited the tube formation of HMEC-1 cells on Matrigel and their migration. Meanwhile, WSS25 (25 microg/mL) nearly completely blocked Id1 expression in the HMEC-1 cells as demonstrated by oligo-angiogenesis microarray analysis and further confirmed by RT-PCR and Western blotting. The BMP/Smad/Id1 signaling was also blocked by WSS25 treatment in the HMEC-1 cells. Importantly, Id1 knock-down in HMEC-1 cells caused the disruption of their tube formation on Matrigel. By employing quartz crystal microbalance (QCM) analysis, we found that WSS25 strongly bound to BMP2. Moreover, WSS25 impaired BMP2 induced tube formation of HMEC-1 cells on Matrigel and angiogenesis in Matrigel transplanted into C57BL6 mice. Furthermore, WSS25 (100 mg/kg) abrogated the growth of HCC cells xenografted in male nude mice. Immunohistochemical analysis showed that both the expression of Id1 and the endothelial cell marker CD31 were lower in the WSS25 treated tumor tissue than in the control. Therefore, WSS25 is a potential drug candidate for HCC therapy as a tumor angiogenesis inhibitor.

Keywords: WSS25 hepatocellular cancer angiogenesis