The research in my laboratory focuses on the molecular mechanism and signaling pathways that regulate tumor angiogenesis. In gene profile studies of cultured endothelial cells exposed to VEGF-A165, we found that TR3 (mouse homologue, Nur77) was highly upregulated not only in VEGF-A165-stimulated endothelial cells, but also in microvessels in several examples of pathological angiogenesis in vivo, including adenovirus VEGF-A164-induced angiogenesis, skin wound healing and tumors. growth of B16 melanoma was completely inhibited in Nur77 knock out (nur77-/-) mice. Overexpression of TR3/Nur77 was sufficient by itself to induce angiogenesis and also that TR3/Nur77 had an essential role in VEGF-A165-induced angiogenesis.
Down syndrome candidate region 1 (DSCR1) is another gene that is identified to be upregulated by VEGF. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to provide a negative feedback loop that inhibits VEGF-A165-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We found that another DSCR1 isoform, DSCR1-1L, was also upregulated by VEGF-A165 in cultured endothelial cells and is strongly expressed in several types of pathological angiogenesis in vivo. Moreover, DSCR1-1L and DSCR1-4 were expressed in tumor microvascular structure, not in tumor cells, nor in normal vessel, either. DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for anti-angiogenesis therapy.
Another project is to study the role of protein kinase D in VEGF-induced angiogenesis. We demonstrate that PKD interacts with PLCg and becomes tyrosine phosphorylated upon VEGF stimulation, leading to PLCg activation and angiogenic response of VEGF-A165.