SEMA3B, a member of class 3 semaphorins, is a tumor suppressor. Competition with vascular endothelial growth factor (VEGF)165 explains a portion of the activity, whereas the VEGF-independent mechanism was not elucidated. We employed a microarray and screened for the genes whose expression was increased by SEMA3B in NCI-H1299 cells. Insulin-like growth factor-binding protein-6 (IGFBP-6), a tumor suppressor, showed greatest difference in the expression level. Introduction of IGFBP-6 cDNA reduced colony formation both on the dish surface and in soft agar. Insulin-like growth factor II, which antagonizes IGFBP-6, partly abrogated the effect. Inhibition of IGFBP-6 by small interfering RNA diminished the sub-G0/G1 population that was induced by SEMA3B and abrogated the growth suppressive effect of SEMA3B. We concluded that IGFBP-6 is the effector of tumor suppressor activity of SEMA3B in NCI-H1299 cells. It has been reported that β-catenin suppresses the expression of IGFBP-6. Introduction of β-catenin into the cells partly abrogated the growth suppressive effect of SEMA3B. Our result indicates that semaphorin signaling and β-catenin signaling converge on IGFBP-6 and antithetically affect their functions.
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We thank Ms Akemi Yokote for technical assistance. This study was supported in part by the following grants-in-aid: 1) for scientific research (nos. 18390242 and 16590738) from the Japan Society for the Promotion of Science and 2) for Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare, Japan.
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Koyama, N., Zhang, J., Huqun et al. Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3B. Oncogene 27, 6581–6589 (2008). https://doi.org/10.1038/onc.2008.263
- semaphorin 3B
- insulin-like growth factor-binding protein-6
- tumor suppression
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