HISTAMINE H4 RECEPTOR AS A NOVEL THERAPEUTIC TARGET FOR THE TREATMENT OF LEYDIG CELL TUMORS IN PREPUBERTAL BOYS

MONDILLO CAROLINA; BELGOROSKY, ALICIA; MARCOS, ALEJANDRA; VARELA, MARÍA LUISA; PIGNATARO OMAR P; PONZIO, ROBERTO; HARO DURAND, LUIS; BERENSZTEIN, ESPERANZA; RIVAROLA, MARCO AURELIO; BESIO MORENO MARCOS; ABIUSO, ADRIANA MARÍA BELÉN

Buenos Aires

Congreso; LXII Reunión Científica de la Sociedad Argentina de Investigación Clínica; 2017

SAIC

(524) HISTAMINE H4 RECEPTOR AS A NOVEL THERAPEUTIC TARGET FOR THE TREATMENT OF LEYDIG CELL TUMORS IN PREPUBERTAL BOYS Adriana María Belén Abiuso (1), María Luisa Varela (1), Luis Haro Durand (1), Marcos Besio Moreno (1), Alejandra Marcos (1), Roberto Ponzio (2), Marco Aurelio Rivarola (3), Alicia Belgorosky (3), Omar Pedro Pignataro (1), Esperanza Berensztein (3), Carolina Mondillo (1) (1) Laboratorio de Endocrinología Molecular y Transducción de Señales, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Vuelta de Obligado 2490 (C1428ADN), Buenos Aires, Argentina. (2) Facultad de Medicina, Universidad de Buenos Aires. C.A.B.A., Argentina. (3) Servicio de Endocrinología, Hospital de Pediatría ?Prof. Dr.Juan P. Garrahan?, Combate de los Pozos 1881 (C1245 AAM) C.A.B.A., Argentina. Leydig cell tumors (LCT) are rare endocrine tumors of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/ or gynecomastia, in adults. The evidence so far points to aromatase (CYP19) overexpression and excessive estrogen (E2) and IGF−1 production as responsible for Leydig cell tumorigenesis. While LCT are usually benign, the malignant phenotype in adults responds poorly to chemo/radiotherapy, highlighting the need to identify new targets for treatment. Herein, we studied the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCT. Experiments were performed in R2C rat Leydig tumor cells (R2C), the best-known in vitro model for Leydigioma. The expression of HRH4, StAR and CYP19 was evaluated by qPCR and Western Blot. P4 and E2 levels were quantified by RIA, and cell proliferation was determined by 3H-Thymidine incorporation. The angiogenic capacity of R2C and the effect of HRH4 agonist treatment on this capacity were evaluated in vitro and in vivo, using human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Also, HRH4 immunoexpression was studied in 2 human LCT versus normal human testis samples (NHTS) belonging to four different age groups: neonatal, n=2; infantile, n=1; juvenile, n=3 and pubertal, n=3. E2 and IGF-1 negatively regulated HRH4 mRNA and protein levels in R2C. In agreement, HRH4 expression was weak in LCT but moderate to strong, and confined to the interstitium, in all the NHTS analyzed. No HRH4 was detected in seminiferous tubules or germ cells. Treatment of R2C with HRH4 agonists inhibited StAR expression (p