Semaphorin 3B Gene Suppresses Tumor Growth Through the p53 Signaling Pathway and Neuropilin Receptors
The semaphorin family has been demonstrated to possess tumor suppressor activity; semaphorin 3B (SEMA3B) is differentially expressed in several types of tumors, and has been identified as a tumor suppressor gene. SEMA3B is shown to be a target gene of p53, and it suppresses tumor growth through the p53 signaling pathway. The mechanisms underlying tumor suppression by SEMA3B include neuropilin receptors (NRP1 and NRP2), which reduce the action of vascular endothelial growth factor (VEGF), thus, inhibiting tumor angiogenesis. Deficiency or down-regulation of SEMA3B expression can be found in a variety of malignant tumors including lung cancer, ovarian cancer, nervous system tumors, and hepatobiliary tumors, and this suppression involves methylation, loss of heterozygosity (LOH) and enzyme cleavage. This review summarizes recent research approaches on the tumor suppression effects and mechanisms of SEMA3B.
Semaphorin 3B Gene Suppresses Tumor Growth Through the p53 Signaling Pathway and Neuropilin Receptors, American Journal of Clinical and Experimental Medicine.
Vol. 5, No. 6,
2017, pp. 234-238.
Sang C, Zhang Y, Chen F, Huang P, Qi J, Wang P, Zhou Q, Kang H, Cao X and Guo L: Tumor necrosis factor alpha suppresses osteogenic differentiation of MSCs by inhibiting semaphorin 3B via Wnt/beta-catenin signaling in estrogen-deficiency induced osteoporosis. Bone 84: 78-87, 2016.
Arbeille E, Reynaud F, Sanyas I, Bozon M, Kindbeiter K, Causeret F, Pierani A, Falk J, Moret F and Castellani V: Cerebrospinal fluid-derived Semaphorin 3B orients neuroepithelial cell divisions in the apicobasal axis. Nat Commun 6: 6366, 2015.
Ochi K, Mori T, Toyama Y, Nakamura Y and Arakawa H: Identification of semaphoring 3B as a direct target of p53. Neoplasia 4: 82-87, 2002.
Wang H, Jiang L, Gao B and Dong M: Alteration of serum semaphorin 3B levels in preeclampsia. Clin Chim Acta 455: 60-63, 2016.
Joseph D, Ho SM and Syed V: Hormonal regulation and distinct functions of semaphorin-3B and semaphorin-3F in ovarian cancer. Mol Cancer Ther 9: 499-509, 2010.
Fonseca FP, Bingle L, Santos-Silva AR, Lopes MA, de Almeida OP, de Andrade BA, Mariano FV, Kowalski LP, Rangel AL, et al: Semaphorins and neuropilins expression in salivary gland tumors. J Oral Pathol Med 45: 119-126, 2016.
Castro-Rivera E, Ran S, Thorpe P and Minna JD: Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci U S A 101: 11432-11437, 2004.
Smardova J, Liskova K, Ravcukova B, Malcikova J, Hausnerova J, Svitakova M, Hrabalkova R, Zlamalikova L, Stano-Kozubik K, et al: Complex analysis of the p53 tumor suppressor in lung carcinoma. Oncol Rep 35: 1859-1867, 2016.
Loginov VI, Dmitriev AA, Senchenko VN, Pronina IV, Khodyrev DS, Kudryavtseva AV, Krasnov GS, Gerashchenko GV, Chashchina LI, et al: Tumor Suppressor Function of the SEMA3B Gene in Human Lung and Renal Cancers. PLoS One 10: e0123369, 2015.
Tse C, Xiang RH, Bracht T and Naylor SL: Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. Cancer Res 62: 542-546, 2002.
Tischoff I, Markwarth A, Witzigmann H, Uhlmann D, Hauss J, Mir mohammad sadegh A, Wittekind C, Hengge UR and Tannapfel A: Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int J Cancer 115: 684-689, 2005.
Lin ZF, Shen XY, Lu FZ, Ruan Z, Huang HL and Zhen J: Reveals new lung adenocarcinoma cancer genes based on gene expression. Eur Rev Med Pharmacol Sci 16: 1249-1256, 2012.
Kolodkin AL, Matthes DJ and Goodman CS: The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75: 1389-1399, 1993.
Yazdani U and Terman JR: The semaphorins. Genome Biol 7: 211, 2006.
Ito D, Nojima S and Kumanogoh A: The role of semaphorin family in immune systems. Nihon Rinsho Meneki Gakkai Kaishi 37: 1-10, 2014.
Kong-Beltran M, Stamos J and Wickramasinghe D: The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell 6: 75-84, 2004.
Jin MS, Park IA, Kim JY, Chung YR, Im SA, Lee KH, Moon HG, Han W, Noh DY and Ryu HS: New insight on the biological role of p53 protein as a tumor suppressor: re-evaluation of its clinical significance in triple-negative breast cancer. Tumour Biol 37: 11017-11024, 2016.
Moriya J, Minamino T, Tateno K, Okada S, Uemura A, Shimizu I, Yokoyama M, Nojima A, Okada M, Koga H and Komuro I: Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis. Circ Res 106: 391-398, 2010.
Chen R, Zhuge X, Huang Z, Lu D, Ye X, Chen C, Yu J and Lu G: Analysis of SEMA3B methylation and expression patterns in gastric cancer tissue and cell lines. Oncol Rep 31: 1211-1218, 2014.
Ito M, Ito G, Kondo M, Uchiyama M, Fukui T, Mori S, Yoshioka H, Ueda Y, Shimokata K and Sekido Y: Frequent inactivation of RASSF1A, BLU, and SEMA3B on 3p21.3 by promoter hypermethylation and allele loss in non-small cell lung cancer. Cancer Lett 225: 131-139, 2005.
Zhang L, Wang JN, Tang JM, Kong X, Yang JY, Zheng F, Guo LY, Huang YZ, Zhang L, et al: VEGF is essential for the growth and migration of human hepatocellular carcinoma cells. Mol Biol Rep 39: 5085-5093, 2012.
Varshavsky A, Kessler O, Abramovitch S, Kigel B, Zaffryar S, Akiri G and Neufeld G: Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res 68: 6922-6931, 2008.
Jauhiainen S, Hakkinen SK, Toivanen PI, Heinonen SE, Jyrkkanen HK, Kansanen E, Leinonen H, Levonen AL and Yla-Herttuala S: Vascular endothelial growth factor (VEGF)-D stimulates VEGF-A, stanniocalcin-1, and neuropilin-2 and has potent angiogenic effects. Arterioscler Thromb Vasc Biol 31: 1617-1624, 2011.
Tomizawa Y, Sekido Y, Kondo M, Gao B, Yokota J, Roche J, Drabkin H, Lerman MI, Gazdar AF and Minna JD: Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A 98: 13954-13959, 2001.
de Lange R, Dimoudis N and Weidle UH: Identification of genes associated with enhanced metastasis of a large cell lung carcinoma cell line. Anticancer Res 23: 187-194, 2003.
Beuten J, Garcia D, Brand TC, He X, Balic I, Canby-Hagino E, Troyer DA, Baillargeon J, Hernandez J, et al: Semaphorin 3B and 3F single nucleotide polymorphisms are associated with prostate cancer risk and poor prognosis. J Urol 182: 1614-1620, 2009.
Karayan-Tapon L, Wager M, Guilhot J, Levillain P, Marquant C, Clarhaut J, Potiron V and Roche J: Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker? Br J Cancer 99: 1153-1160, 2008.
Chen HC, Huang HY, Chen YL, Lee KD, Chu YR, Lin PY, Hsu CC, Chu PY, Huang TH, et al: Methylation of the Tumor Suppressor Genes HIC1 and RassF1A Clusters Independently From the Methylation of Polycomb Target Genes in Colon Cancer. Ann Surg Oncol 2015.
Sheng Y, Wang H, Liu D, Zhang C, Deng Y, Yang F, Zhang T and Zhang C: Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma. Gynecol Oncol 140: 145-151, 2016.
Xie M, Wu X, He C, Zhang J and Zhang J: Ski is silenced by methylation and acts as tumor suppressor in non-small cell lung cancer. Oncotarget 2015.
Gao X, Tang C, Shi W, Feng S, Qin W, Jiang T and Sun Y: Semaphorin-3F functions as a tumor suppressor in colorectal cancer due to regulation by DNA methylation. Int J Clin Exp Pathol 8: 12766-12774, 2015.
Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Williams NN, Kaiser LR and Croce CM: Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. Cancer Res 63: 3352-3355, 2003.
Nair PN, McArdle L, Cornell J, Cohn SL and Stallings RL: High-resolution analysis of 3p deletion in neuroblastoma and differential methylation of the SEMA3B tumor suppressor gene. Cancer Genet Cytogenet 174: 100-110, 2007.
Yi HM, Li H, Peng D, Zhang HJ, Wang L, Zhao M, Yao KT and Ren CP: Genetic and epigenetic alterations of LTF at 3p21.3 in nasopharyngeal carcinoma. Oncol Res16: 261-272, 2006.
Riquelme E, Tang M, Baez S, Diaz A, Pruyas M, Wistuba, II and Corvalan A: Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma. Cancer Lett 250: 100-106, 2007.
Osada R, Horiuchi A, Kikuchi N, Ohira S, Ota M, Katsuyama Y and Konishi I: Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. Hum Pathol 37: 1414-1425, 2006.
Rolny C, Capparuccia L, Casazza A, Mazzone M, Vallario A, Cignetti A, Medico E, Carmeliet P, Comoglio PM and Tamagnone L: The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med 205: 1155-1171, 2008.