Abstract:
Leydig-cell tumours (LCTs) are rare endocrine tumours of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/or gynaecomastia, in adults. So far, scientific evidence points to aromatase (CYP19) overexpression and excessive oestrogen and insulin-like growth factor (IGF) –1 production as responsible for Leydig-cell tumourigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumour cells, a well-documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, oestrogen receptor (ER) α ERβ androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF-1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERβ were overexpressed compared with NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs. © 2017 Elsevier Ltd
Registro:
Documento: |
Artículo
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Título: | Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
Autor: | Abiuso, A.M.B.; Varela, M.L.; Haro Durand, L.; Besio Moreno, M.; Marcos, A.; Ponzio, R.; Rivarola, M.A.; Belgorosky, A.; Pignataro, O.P.; Berensztein, E.; Mondillo, C. |
Filiación: | Laboratorio de Endocrinología Molecular y Transducción de Señales, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Vuelta de Obligado 2490, Buenos Aires, C1428ADN, Argentina Laboratorio de Patología y Farmacología Molecular, IBYME-CONICET, Buenos Aires, Argentina Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Servicio de Endocrinología, Hospital de Pediatría “Prof. Dr.Juan P. Garrahan”, Buenos Aires, Argentina Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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Palabras clave: | Angiogenesis; CYP19 aromatase; Histamine; Histamine receptor H4; Leydig-cell tumour; Oestradiol; Steroidogenesis; androgen receptor; cytochrome P450 family 19; estrogen receptor alpha; estrogen receptor beta; histamine H4 receptor; somatomedin C receptor; androgen receptor; angiogenesis inhibitor; antineoplastic agent; AR protein, human; aromatase; clobenpropit; CYP19A1 protein, human; ESR2 protein, human; estrogen receptor alpha; estrogen receptor alpha, human; estrogen receptor beta; guanidine derivative; histamine agonist; histamine H4 receptor; IGF1R protein, human; imidazole derivative; S-(2-guanidylethyl)isothiourea; somatomedin receptor; steroid synthesis inhibitor; thiourea; angiogenesis; animal cell; animal cell culture; animal experiment; animal model; Article; cell proliferation; cell proliferation assay; chorioallantoic membrane assay; controlled study; drug targeting; human; human cell; human tissue; immunohistochemistry; in vitro study; in vivo study; Leydig cell tumor; male; nonhuman; prepuberty; priority journal; protein expression; R2C cell line; rat; reverse transcription polymerase chain reaction; steroidogenesis; testis tissue; tumor cell; umbilical vein endothelial cell; Western blotting; age; agonists; analogs and derivatives; animal; Coturnix; drug effect; embryology; infant; Leydig cell tumor; metabolism; molecularly targeted therapy; neovascularization (pathology); pathology; signal transduction; testis tumor; tumor cell line; Age Factors; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Aromatase; Cell Line, Tumor; Cell Proliferation; Coturnix; Estrogen Receptor alpha; Estrogen Receptor beta; Guanidines; Histamine Agonists; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Infant; Leydig Cell Tumor; Male; Molecular Targeted Therapy; Neovascularization, Pathologic; Rats; Receptors, Androgen; Receptors, Histamine H4; Receptors, Somatomedin; Signal Transduction; Steroid Synthesis Inhibitors; Testicular Neoplasms; Thiourea |
Año: | 2018
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Volumen: | 91
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Página de inicio: | 125
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Página de fin: | 135
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DOI: |
http://dx.doi.org/10.1016/j.ejca.2017.12.003 |
Título revista: | European Journal of Cancer
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Título revista abreviado: | Eur. J. Cancer
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ISSN: | 09598049
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CODEN: | EJCAE
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CAS: | histamine H4 receptor, 272100-58-0; aromatase, 9039-48-9; clobenpropit, 145231-45-4; thiourea, 62-56-6; Angiogenesis Inhibitors; Antineoplastic Agents; AR protein, human; Aromatase; clobenpropit; CYP19A1 protein, human; ESR2 protein, human; Estrogen Receptor alpha; estrogen receptor alpha, human; Estrogen Receptor beta; Guanidines; Histamine Agonists; IGF1R protein, human; Imidazoles; Receptors, Androgen; Receptors, Histamine H4; Receptors, Somatomedin; S-(2-guanidylethyl)isothiourea; Steroid Synthesis Inhibitors; Thiourea
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09598049_v91_n_p125_Abiuso |
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Citas:
---------- APA ----------
Abiuso, A.M.B., Varela, M.L., Haro Durand, L., Besio Moreno, M., Marcos, A., Ponzio, R., Rivarola, M.A.,..., Mondillo, C.
(2018)
. Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys. European Journal of Cancer, 91, 125-135.
http://dx.doi.org/10.1016/j.ejca.2017.12.003---------- CHICAGO ----------
Abiuso, A.M.B., Varela, M.L., Haro Durand, L., Besio Moreno, M., Marcos, A., Ponzio, R., et al.
"Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys"
. European Journal of Cancer 91
(2018) : 125-135.
http://dx.doi.org/10.1016/j.ejca.2017.12.003---------- MLA ----------
Abiuso, A.M.B., Varela, M.L., Haro Durand, L., Besio Moreno, M., Marcos, A., Ponzio, R., et al.
"Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys"
. European Journal of Cancer, vol. 91, 2018, pp. 125-135.
http://dx.doi.org/10.1016/j.ejca.2017.12.003---------- VANCOUVER ----------
Abiuso, A.M.B., Varela, M.L., Haro Durand, L., Besio Moreno, M., Marcos, A., Ponzio, R., et al. Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys. Eur. J. Cancer. 2018;91:125-135.
http://dx.doi.org/10.1016/j.ejca.2017.12.003