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1.
Anticancer Res ; 41(9): 4211-4214, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475040

RESUMO

BACKGROUND: Testicular cancer constitutes 1.0% of male cancer and typically carries a good prognosis. As far as we are aware, the role for hydrogen sulfide in testicular cancer and the level of hydrogen sulfide-synthesizing enzyme have never been addressed. Here we examined cystathionine gamma-lyase (CSE) expression in several germ-cell testicular tumors. MATERIALS AND METHODS: Tissue microarrays were employed to examine CSE expression in 32 benign testicular samples, 88 testicular seminomas, 34 embryonal carcinomas, 4 mature teratomas, and 16 yolk sac tumors, and CSE expression was compared to that seen in benign testicular tissue. RESULTS: Compared to benign testicular tissue, CSE expression was increased in all three types of testicular neoplasm but not in mature teratomas. Highest CSE expression was identified in embryonal carcinomas, which often show a relatively aggressive clinical course. CONCLUSION: For the first time, we show that CSE is increased in several common testicular germ-cell tumor types.


Assuntos
Carcinoma Embrionário/metabolismo , Cistationina gama-Liase/metabolismo , Tumor do Seio Endodérmico/metabolismo , Neoplasias Testiculares/metabolismo , Regulação para Cima , Estudos de Casos e Controles , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Seminoma , Análise Serial de Tecidos
2.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360857

RESUMO

Herein, for the first time, the potential relationships between the cytoskeleton-associated proteins DAAM1 and PREP with different testicular disorders, such as classic seminoma (CS), Leydig cell tumor (LCT), and Sertoli cell-only syndrome (SOS), were evaluated. Six CS, two LCT, and two SOS tissue samples were obtained during inguinal exploration in patients with a suspect testis tumor based on clinical examination and ultrasonography. DAAM1 and PREP protein levels and immunofluorescent localization were analyzed. An increased DAAM1 protein level in CS and SOS as compared to non-pathological (NP) tissue was observed, while LCT showed no significant differences. Conversely, PREP protein level increased in LCT, while it decreased in CS and SOS compared to NP tissue. These results were strongly supported by the immunofluorescence staining, revealing an altered localization and signal intensity of DAAM1 and PREP in the analyzed samples, highlighting a perturbed cytoarchitecture. Interestingly, in LCT spermatogonia, a specific DAAM1 nuclear localization was found, probably due to an enhanced testosterone production, as confirmed by the increased protein levels of steroidogenic enzymes. Finally, although further studies are needed to verify the involvement of other formins and microtubule-associated proteins, this report raised the opportunity to indicate DAAM1 and PREP as new potential markers, supporting the cytoskeleton dynamics changes occurring during normal and/or pathological cell differentiation.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Proteínas Mitocondriais/metabolismo , Seminoma/metabolismo , Serina Endopeptidases/metabolismo , Neoplasias Testiculares/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Biomarcadores Tumorais/metabolismo , Citoesqueleto/metabolismo , Humanos , Masculino , Espermatogônias/metabolismo
3.
Nat Commun ; 12(1): 4487, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301922

RESUMO

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Embrionárias de Células Germinativas/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Testiculares/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico , Redes Reguladoras de Genes/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Neoplasias Embrionárias de Células Germinativas/metabolismo , Mapas de Interação de Proteínas/genética , Neoplasias Testiculares/metabolismo
4.
PLoS One ; 16(5): e0251028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33945571

RESUMO

SPATS1 (spermatogenesis-associated, serine-rich 1) is an evolutionarily conserved, testis-specific protein that is differentially expressed during rat male meiotic prophase. Some reports have suggested a link between SPATS1 underexpression/mutation and human pathologies such as male infertility and testicular cancer. Given the absence of functional studies, we generated a Spats1 loss-of-function mouse model using CRISPR/Cas9 technology. The phenotypic analysis showed no overt phenotype in Spats1-/- mice, with both males and females being fertile. Flow cytometry and histological analyses did not show differences in the testicular content and histology between WT and knockout mice. Moreover, no significant differences in sperm concentration, motility, and morphology, were observed between WT and KO mice. These results were obtained both for young adults and for aged animals. Besides, although an involvement of SPATS1 in the Wnt signaling pathway has been suggested, we did not detect changes in the expression levels of typical Wnt pathway-target genes in mutant individuals. Thus, albeit Spats1 alteration might be a risk factor for male testicular health, we hereby show that this gene is not individually essential for male fertility and spermatogenesis in mouse.


Assuntos
Fertilidade/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Espermatogênese/fisiologia , Sequência de Aminoácidos , Animais , Feminino , Infertilidade Masculina/metabolismo , Masculino , Meiose/fisiologia , Camundongos , Camundongos Knockout , Neoplasias Embrionárias de Células Germinativas/metabolismo , Serina/metabolismo , Contagem de Espermatozoides/métodos , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo , Neoplasias Testiculares/metabolismo , Testículo/metabolismo
5.
Adv Anat Pathol ; 28(4): 258-275, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33871428

RESUMO

Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.


Assuntos
Tumor do Seio Endodérmico/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Seminoma/patologia , Teratoma/patologia , Neoplasias Testiculares/patologia , Tumor do Seio Endodérmico/genética , Tumor do Seio Endodérmico/metabolismo , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Seminoma/genética , Seminoma/metabolismo , Teratoma/genética , Teratoma/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo
6.
Toxins (Basel) ; 13(3)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808971

RESUMO

Mammalian animal toxicity of ochratoxin A (OTA) has focused largely in the past half-century on pigs because of initial recognition of it as a principal cause of intermittent growth suppression and renal disease caused by mouldy feed. Subsequent classical toxicology has used laboratory rodents because renal pathology in pigs raised questions concerning possible involvement in the human idiopathic bilateral renal atrophy of Balkan endemic nephropathy for which OTA was a focus of attention for human nephropathy through 1980s and into 2000s. Emphasis on human nephropathy has more recently concerned the plant metabolite aristolochic acid. Recognition that agricultural management can often minimise food and feed-stuff spoilage by OTA-producing Aspergilli and Penicillia has moderated some of the risks for animals. Legislation for human food safety combined with sophisticated analysis generally provides safety in the developed world. Chronic experimental exposure of male rats, in the absence of clinical dis-ease, specifically causes renal cancer. The possibility of this as a unique model for the human has generated considerable experimental evidence which may be more directly relevant for carcinogenesis in the complex kidney than that obtained from biochemical toxicities in vitro. Nevertheless, there does not appear to be any case of human renal or urinary tract cancer for which there is verified etiological proof for causation by OTA, contrary to much claim in the literature. To contribute to such debate, histopathology review of OTA/rat renal cancers, augmented where appropriate by immune profiles, has been completed for all remaining tumours in our research archive. Overall consistency of positivity for vimentin, is matched with occasional positives either for CD10 or the cytokeratin MNF 116. The current situation is discussed. Suggestion that OTA could cause human testicular cancer has also been challenged as unsupported by any experimental findings in rats, where the Leydig cell tumour immune profile does not match that of human germ cell neoplasms.


Assuntos
Testes de Carcinogenicidade , Neoplasias Renais/induzido quimicamente , Ocratoxinas/toxicidade , Neoplasias Testiculares/induzido quimicamente , Animais , Exposição Dietética , Humanos , Queratinas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Neprilisina/metabolismo , Ratos Endogâmicos F344 , Medição de Risco , Fatores de Risco , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Fatores de Tempo , Vimentina/metabolismo
7.
Biochem Biophys Res Commun ; 557: 55-61, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33862460

RESUMO

Dysregulation of the ubiquitin-proteasome pathway is strongly associated with cancer initiation and progression. Speckle-type POZ(pox virus and zinc finger protein) protein(SPOP) is an adapter protein of CUL3-based E3 ubiquitin ligase complexes. Gene expression profiling from the Cancer Genome Atlas (TCGA) suggests that SPOP is downregulated in testicular germ cell tumors (TGCTs), but the specific contribution of this protein remains to be explored. In this study, we show that the germ line-specific factor DPPA2 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin-ligase complex. SPOP specifically binds to a SPOP-binding consensus (SBC) degron located in DPPA2 and targets DPPA2 for degradation via the ubiquitin-proteasome pathway. SPOP downregulation increases the expression of pluripotency markers OCT4 and Nanog but decreases that of early differentiation marker gene Fst. This effect is partly dependent on its activity toward DPPA2. In addition, the dysregulation of SPOP-DPPA2 axis contributes to the malignant transformation phenotypes of TGCT cells.


Assuntos
Neoplasias Embrionárias de Células Germinativas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Testiculares/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitinação , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Proteínas Nucleares/genética , Proteólise , Proteínas Repressoras/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia
8.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923996

RESUMO

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/ß-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of ß-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of ß-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/ß-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/ß-catenin pathway inhibition in GCTs is therefore warranted.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/metabolismo , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/metabolismo , beta Catenina/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Pirazinas/farmacologia , Piridinas/farmacologia , Pirimidinonas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
9.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806352

RESUMO

Lipids play essential roles in numerous cellular processes, including membrane remodeling, signal transduction, the modulation of hormone activity, and steroidogenesis. We chose steroidogenic MA-10 mouse tumor Leydig cells to investigate subcellular lipid localization during steroidogenesis. Electron microscopy showed that cAMP stimulation increased associations between the plasma membrane (PM) and the endoplasmic reticulum (ER) and between the ER and mitochondria. cAMP stimulation also increased the movement of cholesterol from the PM compared to untreated cells, which was partially inhibited when ATPase family AAA-domain containing protein 3 A (ATAD3A), which functions in ER and mitochondria interactions, was knocked down. Mitochondria, ER, cytoplasm, PM, PM-associated membranes (PAMs), and mitochondria-associated membranes (MAMs) were isolated from control and hormone-stimulated cells. Lipidomic analyses revealed that each isolated compartment had a unique lipid composition, and the induction of steroidogenesis caused the significant remodeling of its lipidome. cAMP-induced changes in lipid composition included an increase in phosphatidylserine and cardiolipin levels in PAM and PM compartments, respectively; an increase in phosphatidylinositol in the ER, mitochondria, and MAMs; and a reorganization of phosphatidic acid, cholesterol ester, ceramide, and phosphatidylethanolamine. Abundant lipids, such as phosphatidylcholine, were not affected by hormone treatment. Our data suggested that PM-ER-mitochondria tethering may be involved in lipid trafficking between organelles and indicated that hormone-induced acute steroid production involves extensive organelle remodeling.


Assuntos
Tumor de Células de Leydig/metabolismo , Lipídeos de Membrana/metabolismo , Esteroides/biossíntese , Neoplasias Testiculares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Bucladesina/farmacologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Colesterol/metabolismo , AMP Cíclico/farmacologia , Retículo Endoplasmático/metabolismo , Técnicas de Silenciamento de Genes , Tumor de Células de Leydig/ultraestrutura , Lipidômica , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Neoplasias Testiculares/ultraestrutura
10.
Oxid Med Cell Longev ; 2021: 8026941, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603952

RESUMO

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Proteínas de Membrana/metabolismo , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Testículo/metabolismo , Tiorredoxinas/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Linhagem Celular Tumoral , Humanos , Linfoma Difuso de Grandes Células B/ultraestrutura , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Neoplasias Testiculares/ultraestrutura , Testículo/patologia , Testículo/ultraestrutura
11.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567764

RESUMO

Cripto-1 is a member of the EGF-CFC/FRL1/Cryptic family and is involved in embryonic development and carcinogenesis. We designed a novel anti-Cripto-1 artificial antibody and assessed the recognition to the antigen and the potential to suppress the growth of cancer stem cells. First, single chain antibody clones were isolated by bio-panning with the affinity to recombinant Cripto-1 protein from our original phage-display library. Then, the variable regions of heavy chain VH and light chain VL in each clone were fused to constant regions of heavy chain CH and light chain CL regions respectively. These fused genes were expressed in ExpiCHO-S cells to produce artificial humanized antibodies against Cripto-1. After evaluation of the expression levels, one clone was selected and the anti-Cripto-1 antibody was produced and purified. The purified antibody showed affinity to recombinant Cripto-1 at 1.1 pmol and immunoreactivity to cancer tissues and cell lines. The antibody was available to detect the immunoreactivity in tissue microarrays of malignant tumors as well as in Cripto-1 overexpressing cells. Simultaneously, the antibody exhibited the potential to suppress the growth of human colon cancer derived GEO cells overexpressing Cripto-1 with IC50 at approximately 110 nM. The artificially humanized antibody is proposed to be a good candidate to target cancer cells overexpressing Cripto-1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas Ligadas por GPI/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Proteínas de Neoplasias/imunologia , Teratocarcinoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Sequência de Aminoácidos , Anticorpos Monoclonais Humanizados/imunologia , Antineoplásicos/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Masculino , Homologia de Sequência , Teratocarcinoma/imunologia , Teratocarcinoma/metabolismo , Teratocarcinoma/patologia , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Células Tumorais Cultivadas
12.
Asian Pac J Cancer Prev ; 22(1): 75-84, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507682

RESUMO

BACKGROUND: Testicular cancer is a public health problem. The goal of this study was to demonstrate the efficacy of quercetin treatment on N-nitroso-N-methyl-urea (MNU)-induced testicular carcinogenesis alone or in combination with cisplatin-treatment. METHODS: In total 70 adult male albino rats were categorized into six groups, control, quercetin-treatment (10 mg/kg body weight), cisplatin-treatment (2 mg/kg. body weight), cisplatin and quercetin-treatment, MNU-treatment, MNU plus quercetin-treatment and MNU plus quercetin and cisplatin-treatment. Treatment with quercetin and/or cisplatin was performed after 2 months of MNU induced testicular carcinogenesis. The studied groups were euthanized and sacrificed and their testes were examined for gene expression, biochemical, histological and immunohistochemically analysis, inflammation and apoptosis of germ cells. RESULTS: The fertility of the rats subjected to MNU carcinogenesis was impaired following cisplatin and/or quercetin-treatment. Cisplatin-treatment reduced the fertility rate and improved after quercetin-treatment. Quercetin-treatment decreased the sharp increase in RNA expression of BAX and MPO in both cisplatin-toxicated testes and after MNU carcinogenesis induction. In addition, the testicular levels of testosterone and SOD increased in parallel with depletion of MDA, IL-6, AFP and caspase-3 levels in MNU and/or cisplatin-treatment after -quercetin-treatment. The testicular structure of the cisplatin-treated group recovered their dividing germ and sperm differentiation after-quercetin-treatment. While, there was a great appearance of flourishing germ cell of MNU carcinogenesis post quercetin therapy, there was still a lack of sperm differentiation.  Conclusion: Quercetin-treatment showed increased cisplatin activity and decreased testicular carcinogenesis due to anti-neoplastic and antioxidant activities.


Assuntos
Carcinogênese/efeitos dos fármacos , Cisplatino/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metilnitrosoureia/toxicidade , Quercetina/farmacologia , Neoplasias Testiculares/tratamento farmacológico , Alquilantes/toxicidade , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Proliferação de Células , Quimioterapia Combinada , Perfilação da Expressão Gênica , Masculino , Ratos , Ratos Wistar , Neoplasias Testiculares/induzido quimicamente , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia
13.
Virchows Arch ; 478(4): 727-734, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33140129

RESUMO

Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series-the largest so far reported-of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.


Assuntos
Biomarcadores Tumorais/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Testiculares/patologia , Adulto , Teorema de Bayes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/metabolismo , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/metabolismo
14.
Andrologia ; 53(1): e13581, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32323352

RESUMO

The effects of reactive oxygen species on male fertility are governed by the oxidative paradox, defined by a delicate balance between oxidative stress and antioxidant capacity. When regulated appropriately, reactive oxygen species ensure effective function; however, when uninhibited, they represent key players in male factor infertility. Mechanisms responsible for this include oxidative destruction of sperm lipid membranes, damage to gamete DNA both by gene mutation and by direct breakdown of the DNA backbone, mitochondrial dysfunction and apoptotic cell death. Utilizing various male pathologies as case studies, we see ways in which oxidative stress has the potential to impact fertility in a negative way. Varicocele, erectile dysfunction, testicular cancer and even idiopathic male infertility highlight common mechanistic pathways, as well as subtle variations in the ways reactive oxygen species can operate. Oxidative biomarkers have emerged to better study male infertility, predict reproductive success and modify assisted reproductive technologies to minimize oxidative stress.


Assuntos
Infertilidade Masculina , Neoplasias Testiculares , Varicocele , Antioxidantes/metabolismo , Humanos , Infertilidade Masculina/metabolismo , Masculino , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/metabolismo , Neoplasias Testiculares/metabolismo , Varicocele/metabolismo
15.
Exp Cell Res ; 398(2): 112405, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33271127

RESUMO

Nuclear SOX9 is essential for Sertoli cell differentiation and the development of a testis. Exposure of Sertoli cells to exogenous oestrogen causes cytoplasmic retention of SOX9, inhibiting testis development and promoting ovarian development. The cytoplasmic localisation of SOX9 requires a stabilised microtubule network and a key MAPK complex, ERK1/2, is responsive to oestrogen and known to affect the microtubule network. We hypothesised that oestrogen could stabilise microtubules through the activation of ERK1/2 to promote the cytoplasmic retention of SOX9. Treatment of human testis-derived NT2/D1 cells for 30 min with oestrogen rapidly activated ERK1/2, stabilised the microtubule network and increased cytoplasmic localisation of SOX9. The effects of oestrogen on SOX9 and tubulin were blocked by the ERK1/2 inhibitor U0126, demonstrating that ERK1/2 mediates the stabilisation of microtubules and cytoplasmic retention of SOX9 by oestrogen. Together, these data revealed a previously unknown mechanism for oestrogen in impacting MAPK signalling to block SOX9 bioavailability and the differentiation of Sertoli cells.


Assuntos
Microtúbulos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fatores de Transcrição SOX9/metabolismo , Neoplasias Testiculares/metabolismo , Disponibilidade Biológica , Humanos , Masculino , Neoplasias Testiculares/patologia , Células Tumorais Cultivadas
16.
J Cell Physiol ; 236(1): 706-713, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32617980

RESUMO

Testicular cancer is the most common solid malignancy among young men. We downloaded data of testicular cancer patients from The Cancer Genome Atlas database to find novel genes in the testicular cancer microenviroment based on ESTIMATE algorithm-derived immune scores. A total of 156 cases of testicular cancer were included in this study and 165 cases of normal testicular tissues were used. We divided the testicular cancer patients into high- and low-score groups based on their immune scores. We identified 1,226 differentially expressed genes (fold change > 2, false discovery rate < 0.05), including 688 downregulated genes and 538 upregulated genes, between these two groups. The top Gene Ontology terms were involved in the immune response-regulating cell surface receptor signaling pathway, immune response-activating cell surface receptor signaling pathway, external side of the plasma membrane, and receptor ligand activity. By performing the Kyoto Encyclopedia of Genes and Genomes analysis, we demonstrated that cAMP signaling pathway was highly enriched among these differentially expressed genes. High expression of LINC01564, LINC02208, ODAM, RNA5SP111, and RNU6-196P were found to be associated with poor overall survival. The expression of genes was further validated by the Human Protein Atlas and only ALB and IFNG were demonstrated to be differentially expressed between testis tissue and testicular cancer tissue.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Testiculares/metabolismo , Transcriptoma/imunologia , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/imunologia , Microambiente Tumoral/imunologia
17.
J Clin Endocrinol Metab ; 106(4): e1775-e1792, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33340048

RESUMO

CONTEXT: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown. OBJECTIVE: This work aimed to investigate the role of CaSR in human spermatozoa. METHODS: We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3',5'-cyclic adenosine 5'-monophosphate (cAMP) in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors. RESULTS: CaSR is expressed in human spermatozoa and is essential for sensing extracellular free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3- and the acrosome reaction, whereas spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3-, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3- activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology. CONCLUSION: CaSR is important for the sensing of Ca2+, Mg2+, and HCO3- in spermatozoa, and loss-of-function may impair male sperm function.


Assuntos
Bicarbonatos/metabolismo , Cálcio/metabolismo , Receptores de Detecção de Cálcio/fisiologia , Espermatozoides/metabolismo , Reação Acrossômica/efeitos dos fármacos , Reação Acrossômica/genética , Adulto , Bicarbonatos/farmacologia , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Estudos de Casos e Controles , Feminino , Humanos , Hipercalcemia/congênito , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hipercalcemia/patologia , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/patologia , Hipocalcemia/genética , Hipocalcemia/metabolismo , Hipocalcemia/patologia , Hipoparatireoidismo/congênito , Hipoparatireoidismo/genética , Hipoparatireoidismo/metabolismo , Hipoparatireoidismo/patologia , Rim/metabolismo , Rim/patologia , Magnésio/metabolismo , Magnésio/farmacologia , Masculino , Mutação , Receptores de Detecção de Cálcio/genética , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia
18.
Cells ; 9(12)2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266100

RESUMO

Filamins are large dimeric F-actin cross-linking proteins, crucial for the mechanosensitive properties of a number of cell types. Due to their interaction with a variety of different proteins, they exert important regulatory functions. However, in the human testis the role of filamins has been insufficiently explored. Immunohistochemical staining of human testis samples identified filamin A (FLNA) in spermatogonia and peritubular myoid cells. Investigation of different testicular tumor samples indicated that seminoma also express FLNA. Moreover, mass spectrometric analyses identified FLNA as one of the most abundant proteins in human seminoma TCam-2 cells. We therefore focused on FLNA in TCam-2 cells, and identified by co-immunoprecipitation LAD1, RUVBL1 and DAZAP1, in addition to several cytoskeletal proteins, as interactors of FLNA. To study the role of FLNA in TCam-2 cells, we generated FLNA-deficient cells using the CRISPR/Cas9 system. Loss of FLNA causes an irregular arrangement of the actin cytoskeleton and mechanical instability, impaired adhesive properties and disturbed migratory behavior. Furthermore, transcriptional activity of typical stem cell factors is increased in the absence of FLNA. In summary, our data suggest that FLNA is crucially involved in balancing stem cell characteristics and invasive properties in human seminoma cells and possibly human testicular germ cells.


Assuntos
Movimento Celular/fisiologia , Citoesqueleto/metabolismo , Filaminas/metabolismo , Seminoma/metabolismo , Células-Tronco/metabolismo , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adulto , Idoso , Autoantígenos/metabolismo , Sistemas CRISPR-Cas/fisiologia , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Colágenos não Fibrilares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias Testiculares/metabolismo , Testículo/metabolismo , Transcrição Genética/fisiologia
19.
BMC Urol ; 20(1): 197, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33317491

RESUMO

BACKGROUND: The neuroendocrine cells can cause a variety of malignancies throughout the human body known as the neuroendocrine tumors (NETs) or carcinoid tumors. The primary testicular carcinoid tumor (PTCT) accounts for less than 1% of the testicular neoplasms and for only 0.2% of all carcinoid tumors representing already a very rare neoplastic entity. Here, we present a patient with a history of an exceptionally rare primary testicular carcinoid tumor, staining positive for Cdx-2 along with a literature review. CASE PRESENTATION: A 44-year old patient without significant past medical history was diagnosed in September 2009 with primary testicular carcinoid tumor, which was surprisingly staining positively for Cdx-2, too. At the time of the initial diagnosis the tumor was already showing histopathological infiltration of veins. DOTA-TATE-PET/CT imaging and endoscopy studies did not show any signs of distant metastases and in particular no gastrointestinal manifestation following no further medical indication for systemic chemotherapy. The continuous and close follow-up of the patient has reached a total of over 10 years at the time of publication remaining in complete remission. CONCLUSION: The diagnosis of primary testicular carcinoid is based on histopathology. The detailed histopathologic assessment of biomarkers based on immunohistochemistry is very important for the classification and the prognosis of the primary testicular carcinoid tumor. Primary testicular carcinoid tumor with Cdx-2 positive stain outlines an exceptionally rare neoplastic entity without a consensus about general follow-up guidelines, requiring close clinical and imaging aftercare and consideration in Cdx-2 positive metastatic tumor of unknown origin.


Assuntos
Tumor Carcinoide/cirurgia , Orquiectomia , Neoplasias Testiculares/cirurgia , Adulto , Fator de Transcrição CDX2/biossíntese , Tumor Carcinoide/metabolismo , Seguimentos , Humanos , Masculino , Indução de Remissão , Neoplasias Testiculares/metabolismo , Fatores de Tempo
20.
Sci Rep ; 10(1): 18938, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144587

RESUMO

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients' response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.


Assuntos
Neoplasias Testiculares/metabolismo , Ciclofilina A/genética , Ciclofilina A/metabolismo , Variações do Número de Cópias de DNA/genética , Genótipo , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mutação/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Análise de Sequência de RNA/métodos , Neoplasias Testiculares/genética , Sequenciamento Completo do Exoma/métodos
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