The possible role of semaphorin 3F, the candidate tumor suppressor gene at 3p21.3, in p53-mediated antiangiogenesis. Free

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Since angiogenesis plays a critical role in tumor formation and progression, antiangiogenesis against tumors is an important strategy for cancer therapy. Although p53 has been believed to be associated with anti-angiogenesis through its target genes including Thrombospondin 1 (TSP1) and Brain-specific angiogenesis 1 (BAI1), the precise mechanism remains to be elucidated. Semaphorin 3F (SEMA3F) plays an important role in neuronal development or differentiation as an axon-guidance molecule, whose gene was initially isolated as a candidate for tumor suppressor gene at chromosome 3p21.3 where loss of heterozygosity was frequently observed in a number of human cancers. Thus far we have reported that SEMA3F is a direct target gene of p53. Here we report the role of SEMA3F in p53-mediated antiangiogenesis in vivo. In nude mice assay, the tumors expressing SEMA3F, which is derived from a lung cancer cell line (H1299), showed much slower growth and contained much fewer blood vessels than the control tumors. Moreover the p53-knock-down tumors derived from a colorectal cancer cell line (LS174T-p53KD) displayed the remarkable enhancement of tumor vessel formation compared to the control tumors (LS174T-control). In the LS-174T-p53KD tumors, the mRNA expression levels of SEMA3F and Neuropilin 2 (NRP2), which is a functional receptor of SEMA3F, were lower than those in the LS174T-control tumors. Interestingly, we found that NRP2 is also a direct target of p53. Over-expression of SEMA3F inhibited the cell proliferation of the NRP2-expressing H1299 cells in vitro. These results indicate that p53 plays an important role in antiangiogenesis by regulating the SEMA3F-NRP2 pathway in both the autocrine and the parecrine fashions.