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Expression, Regulation, and Function of Paired-Box Gene 8 in the Human Placenta and Placental Cancer Cell Lines

Departments of Clinical Science (S.F., T.M., A.S., E.T., R.M.) and Experimental Medicine and Pathology (E.F., A.G.), University of Rome, La Sapienza, 00161 Rome, Italy; Neuromed Institute (A.G.), 86077 Pozzilli, Italy; Department of Clinical and Experimental Medicine (F.A., I.P., D.R.), G. Salvatore, and Department of Farmacobiological Sciences, University of Catanzaro, 88100 Catanzaro, Italy; Department of Science and Biomedical Tecnology (G.T., G.D.), University of Udine, 33100 Udine, Italy; and Departments of Clinical Biology (L.L.), Institut Gustave-Roussy, 94805 Villejuif Cedex, France

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Università degli Studi Roma "La Sapienza," Dipartimento Scienze Cliniche, Clinica Medica, 2 Viale del Policlinico, 155 00161 Roma, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.

Pax proteins are transcriptional regulators that control a variety of developmental decisions in vertebrates. During development, the paired-box gene 8 (PAX8) is expressed in the thyroid, kidney, and several areas of the central nervous system. It is also expressed in the adult thyroid gland, in which it mediates TSH-induced modulation of the expression of important genes, such as those encoding thyroglobulin, thyroperoxidase, and the sodium/iodide symporter (NIS). Thus far, placental expression of PAX8 has been described only in mice. In the present study, we show that PAX8 is also expressed in the human placenta at term. In an in vitro model of placental cancer, the JAR choriocarcinoma cell line, human chorionic gonadotropin (hCG) increased levels of PAX8 mRNA and protein, and gel retardation assays indicated that the up-regulation of PAX8 protein expression is associated with an increase in its DNA-binding activity. The effects of hCG were mimicked by forskolin, indicating that they are cAMP dependent. Levels of mRNA for the Wilms’ tumor 1 (WT1) and NIS genes were increased in JAR cells by hCG treatment, whereas overexpression of PAX8 increased only levels of WT1 mRNA. In cells transfected with PAX8-specific small interfering RNA, the stimulatory effects of hCG on WT1 mRNA levels were abolished, but hormonal enhancement of NIS mRNA levels was unchanged. These findings indicate that, in JAR cells, hCG activates a cAMP-dependent pathway that can up-regulate WT1 expression through PAX8.

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