PAX3-FKHR Regulates the Expression of Pleiotrophin to Mediate Motility in Alveolar Rhabdomyosarcoma Cells
Keywords:Rhabdomyosarcoma, PAX3-FKHR, PTN, motility, metastasis.
More than 80% of the aggressive alveolar rhabdomyosarcoma (ARMSs) harbor a PAX3-FKHR fusion transcription factor, which regulates cell motility and promotes metastasis. Our hypothesis is that PAX3-FKHR regulates cell motility by regulating the expression of its transcriptional targets that are also its downstream effectors, which if identified, may lead to novel therapeutic approaches for treating ARMS. Here we report that PAX3-FKHR regulates the expression of pleiotrophin (PTN) by binding specifically to a paired-box domain binding-site in the PTN promoter, indicating that PTN is a transcriptional target of PAX3-FKHR. Significantly, we show that PTN regulates ARMS cell motility. Taken together, we have identified PTN as a novel transcriptional target of PAX3-FKHR that promotes ARMS cell motility. PTN may be a novel therapeutic target for the treatment of ARMS.
Linardic CM. PAX3-FOXO1 fusion gene in rhabdomyosarcoma. Cancer Lett 2008; 270: 10-8. http://dx.doi.org/10.1016/j.canlet.2008.03.035
Kikuchi K, Tsuchiya K, Otabe O, et al. Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma. Biochem Biophys Res Commun 2008; 365: 568-74. http://dx.doi.org/10.1016/j.bbrc.2007.11.017
Ebauer M, Wachtel M, Niggli FK, Schafer BW. Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR. Oncogene 2007; 26: 7267-81. http://dx.doi.org/10.1038/sj.onc.1210525
Xia SJ, Holder DD, Pawel BR, Zhang C, Barr FG. High expression of the PAX3-FKHR oncoprotein is required to promote tumorigenesis of human myoblasts. Am J Pathol 2009; 175: 2600-8. http://dx.doi.org/10.2353/ajpath.2009.090192
Zeng FY, Cui J, Liu L, Chen T. PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis. Cancer Lett 2009; 284: 157-64. http://dx.doi.org/10.1016/j.canlet.2009.04.016
Zeng FY, Dong H, Cui J, Liu L, Chen T. Glycogen synthase kinase 3 regulates PAX3-FKHR-mediated cell proliferation in human alveolar rhabdomyosarcoma cells. Biochem Biophys Res Commun 2010; 391: 1049-55. http://dx.doi.org/10.1016/j.bbrc.2009.12.017
Liu L, Wang YD, Wu J, Cui J, Chen T. Carnitine palmitoyltransferase 1A (CPT1A): a transcriptional target of PAX3-FKHR and mediates PAX3-FKHR-dependent motility in alveolar rhabdomyosarcoma cells. BMC Cancer 2012; 12: 154. http://dx.doi.org/10.1186/1471-2407-12-154
Pondugula SR, Tong AA, Wu J, Cui J, Chen T. Protein phosphatase 2Cbetal regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells. Drug Metab Dispos 2010; 38: 1411-6. http://dx.doi.org/10.1124/dmd.110.032128
Lam KK, Chiu PC, Chung MK, et al. Glycodelin-A as a modulator of trophoblast invasion. Hum Reprod 2009; 24: 2093-103. http://dx.doi.org/10.1093/humrep/dep205
Cao L, Yu Y, Bilke S, et al. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res 2010; 70: 6497-508. http://dx.doi.org/10.1158/0008-5472.CAN-10-0582
Zhang L, Wang C. Identification of a new class of PAX3-FKHR target promoters: a role of the Pax3 paired box DNA binding domain. Oncogene 2007; 26: 1595-605. http://dx.doi.org/10.1038/sj.onc.1209958
Zhang Y, Wang C. Nephroblastoma overexpressed (NOV/CCN3) gene: a paired-domain-specific PAX3-FKHR transcription target that promotes survival and motility in alveolar rhabdomyosarcoma cells. Oncogene 2011; 30: 3549-62. http://dx.doi.org/10.1038/onc.2011.69
Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diverse functions and a novel signaling pathway. Arch Biochem Biophys 2002; 397: 162-71. http://dx.doi.org/10.1006/abbi.2001.2705
Perez-Pinera P, Chang Y, Deuel TF. Pleiotrophin, a multifunctional tumor promoter through induction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromal fibroblasts. Cell Cycle 2007; 6: 2877-83. http://dx.doi.org/10.4161/cc.6.23.5090
Lu KV, Jong KA, Kim GY, et al. Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem 2005; 280: 26953-64. http://dx.doi.org/10.1074/jbc.M502614200
Jager R, List B, Knabbe C, et al. Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients. Br J Cancer 2002; 86: 858-63. http://dx.doi.org/10.1038/sj.bjc.6600202
Feng ZJ, Gao SB, Wu Y, Xu XF, Hua X, Jin GH. Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP beta/zeta signaling by menin. Oncogene 2010; 29, 5416-26. http://dx.doi.org/10.1038/onc.2010.282
Mikelis C, Sfaelou E, Koutsioumpa M, Kieffer N, Papadimitriou E. Integrin alpha(v)beta(3) is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase beta/zeta. FASEB J: Official Publication of the Federation of American Societies for Experimental Biology 2009; 23: 1459-69.