Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys
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) overe...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09598049_v91_n_p125_Abiuso http://hdl.handle.net/20.500.12110/paper_09598049_v91_n_p125_Abiuso |
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paper:paper_09598049_v91_n_p125_Abiuso2023-06-08T15:57:09Z Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys 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 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 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09598049_v91_n_p125_Abiuso http://hdl.handle.net/20.500.12110/paper_09598049_v91_n_p125_Abiuso |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| topic_facet |
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 |
| description |
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 |
| title |
Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| title_short |
Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| title_full |
Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| title_fullStr |
Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| title_full_unstemmed |
Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys |
| title_sort |
histamine h4 receptor as a novel therapeutic target for the treatment of leydig-cell tumours in prepubertal boys |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09598049_v91_n_p125_Abiuso http://hdl.handle.net/20.500.12110/paper_09598049_v91_n_p125_Abiuso |
| _version_ |
1768544922470711296 |