Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 4; pp. 1451 - 1460
• Main Authors: FUTAMURA, Manabu, KAMINO, Hiroki, MIYAMOTO, Yuji, KITAMURA, Noriaki, NAKAMURA, Yasuyuki, OHNISHI, Shiho, MASUDA, Yoshiko, ARAKAWA, Hirofumi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2007
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Growth Processes - genetics; Cell Line, Tumor; Chromosomes, Human, Pair 3; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, Tumor Suppressor; HCT116 Cells; Humans; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - metabolism; Neoplasms - blood supply; Neoplasms - genetics; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuropilin-2 - metabolism; Pharmacology. Drug treatments; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction; Transcription, Genetic; Tumors; Angiogenesis; TP53 Gene; Candidate gene; Neovascularization; Malignant tumor; Semaphorin; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-2485

Although the regulation of tumor angiogenesis is believed to be one of the core functions of p53, the mechanism still remains to be elucidated. Here, we report that semaphorin 3F (SEMA3F), an axon guidance molecule, is involved in p53-regulated antiangiogenesis. The expression level of SEMA3F mRNA was increased by both exogenous and endogenous p53. Chromatin immunoprecipitation assay indicated that a potent p53-binding sequence in intron 1 of SEMA3F interacts with p53 and that it has a p53-responsive transcriptional activity. Overexpression of SEMA3F inhibited in vitro cell growth of the lung cancer cell line H1299. In nude mice assay, the size of the H1299 tumors expressing SEMA3F was much smaller, and they showed lesser number of blood vessels as compared with the control tumors. Moreover, tumors derived from the p53-knockdown colorectal cancer cell line LS174T displayed a remarkable enhancement of tumor vessel formation as compared with control tumors containing normal levels of p53. The expression levels of SEMA3F and neuropilin-2 (NRP2), the functional receptor for SEMA3F, in p53-knockdown LS174T tumors were lower than those in the control tumors. Adenovirus-mediated SEMA3F gene transfer induced the remarkable in vitro growth suppression of the stable transformant of H1299 cells, which express high levels of NRP2. These results suggest that p53 negatively regulates tumor vessel formation and cell growth via the SEMA3F-NRP2 pathway.