RESUMEN
Hepatocellular carcinoma (HCC) is a highly heterogeneous liver cancer with significant male biases in incidence, disease progression, and outcomes. Previous studies have suggested that genes on the Y chromosome could be expressed and exert various male-specific functions in the oncogenic processes. In particular, the RNA-binding motif on the Y chromosome (RBMY) gene is frequently activated in HCC and postulated to promote hepatic oncogenesis in patients and animal models. In the present study, immunohistochemical analyses of HCC specimens and data mining of The Cancer Genome Atlas (TCGA) database revealed that high-level RBMY expression is associated with poor prognosis and survival of the patients, suggesting that RBMY could possess oncogenic properties in HCC. To examine the immediate effect(s) of the RBMY overexpression in liver cancer cells, cell proliferation was analyzed on HuH-7 and HepG2 cells. The results unexpectedly showed that RBMY overexpression inhibited cell proliferation in both cell lines as its immediate effect, which led to vast cell death in HuH-7 cells. Transcriptome analysis showed that genes involved in various cell proliferative pathways, such as the RAS/RAF/MAP and PIP3/AKT signaling pathways, were downregulated by RBMY overexpression in HuH-7 cells. Furthermore, in vivo analyses in a mouse liver cancer model using hydrodynamic tail vein injection of constitutively active AKT and RAS oncogenes showed that RBMY abolished HCC development. These findings support the notion that Y-linked RBMY could serve dual tumor-suppressing and tumor-promoting functions, depending on the spatiotemporal and magnitude of its expression during oncogenic processes, thereby contributing to sexual dimorphisms in liver cancer.
Asunto(s)
Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Proliferación Celular/genética , Minería de Datos , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Hígado/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al ARN/genética , RNA-Seq , Transducción de Señal/genética , Análisis de Supervivencia , Análisis de Matrices Tisulares , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The gonadoblastoma gene, testis-specific protein Y-encoded (TSPY), on the Y chromosome and its X-homologue, TSPX, are cell cycle regulators and function as a proto-oncogene and a tumor suppressor respectively in human oncogenesis. TSPY and TSPX competitively bind to the androgen receptor (AR) and AR variants, such as AR-V7, at their conserved SET/NAP domain, and exacerbate and repress the transactivation of the AR/AR-V7 target genes in ligand dependent and independent manners respectively. The inhibitory domain has been mapped to the carboxyl acidic domain of TSPX, truncation of which renders TSPX to be stimulatory while its transposition to the C-terminus of TSPY results in an inhibitory hybrid protein. TSPY and TSPX co-localize with the endogenous AR, in the presence of ligand, on the promoters and differentially regulate the expression of the endogenous AR target genes in the androgen-responsive LNCaP prostate cancer cells. Transcriptome analysis shows that TSPY and TSPX expressions differentially affect significant numbers of canonical pathways, upstream regulators and cellular functions. Significantly, among the common ones, TSPY activates and TSPX inhibits numerous growth-related and oncogenic canonical pathways and cellular functions in the respective cell populations. Hence, TSPY and TSPX exert opposing effects on the transactivation functions of AR and AR-Vs important for various physiological and disease processes sensitive to male sex hormone actions, thereby not only affecting the pathogenesis of male-specific prostate cancer but also likely contributing to sex differences in the health and diseases of man.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Nucleares/genética , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Transcriptoma/genética , Proteínas de Ciclo Celular/biosíntesis , Línea Celular Tumoral , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Proteínas de Unión al ADN , Regulación del Desarrollo de la Expresión Génica , Gonadoblastoma/genética , Humanos , Masculino , Proteínas Nucleares/biosíntesis , Neoplasias de la Próstata/patología , Dominios Proteicos/genética , Proto-Oncogenes Mas , Receptores Androgénicos/biosíntesis , Testículo/crecimiento & desarrollo , Testículo/patología , Activación Transcripcional/genéticaRESUMEN
The Hirschsprung disease (HSCR) is a complex congenital disorder, arising from abnormalities in enteric nervous system (ENS) development. There is a gender disparity among the patients, with the male to female ratio as high as 5 : 1. Loss-of-function mutations of HSCR genes and haploinsufficiency of their gene products are the primary pathogenic mechanisms for disease development. Recent studies identified over half of the HSCR disease susceptibility genes as targets for the sex-determining factor SRY, suggesting that this Y-encoded transcription factor could be involved in sexual dimorphism in HSCR. Among the SRY targets, the tyrosine kinase receptor RET represents the most important disease gene, whose mutations account for half of the familial and up to one-third of the sporadic forms of HSCR. RET is regulated by a distal and a proximal enhancer at its promoter, in which PAX3 and NKX2-1 are the resident transcription factors respectively. We show that the SRY-box 10 (SOX10) co-activator interacts and forms transcriptional complexes with PAX3 and NKX2-1 in a sequence-independent manner and exacerbates their respective transactivation activities on the RET promoter. SRY competitively displaces SOX10 in such transcription complexes and represses their regulatory functions on RET. Hence SRY could be a Y-located negative modifier of RET expression; and if it is ectopically expressed during ENS development, such SRY repression could result in RET protein haploinsufficiency and promotion of HSCR development, thereby contributing to sexual dimorphism in HSCR.
Asunto(s)
Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Factores de Transcripción SOXE/metabolismo , Proteína de la Región Y Determinante del Sexo/metabolismo , Cromosomas Humanos Y/metabolismo , Femenino , Humanos , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Transcripción PAX3 , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Factores de Transcripción SOXE/genética , Caracteres Sexuales , Proteína de la Región Y Determinante del Sexo/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. It is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.
Asunto(s)
Proteínas de Ciclo Celular/genética , Cromosomas Humanos Y/genética , Neoplasias de la Próstata/genética , Sitios de Unión/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Exones , Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Gonadoblastoma/genética , Gonadoblastoma/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Mapeo de Interacción de Proteínas , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Regulación hacia ArribaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1ß was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.
Asunto(s)
Péptidos beta-Amiloides , COVID-19 , Humanos , SARS-CoV-2 , Inflamación , NeuronasRESUMEN
Androgen receptor variant 7 (AR-V7), an AR isoform with a truncated ligand-binding domain, functions as a transcription factor in an androgen-independent manner. AR-V7 is expressed in a subpopulation of hepatocellular carcinoma (HCC), however, its role(s) in this cancer is undefined. In this study, we investigated the potential roles of AR-V7 in hepatocarcinogenesis in vivo in a c-MYC-driven mouse HCC model generated by the hydrodynamic tail-vein injection system. The impacts of AR-V7 on gene expression in mouse HCC were elucidated by RNA-seq transcriptome and ontology analyses. The results showed that AR-V7 significantly exacerbated the c-MYC-mediated oncogenesis in the livers of both sexes. The transcriptome and bioinformatics analyses revealed that AR-V7 and c-MYC synergistically altered the gene sets involved in various cancer-related biological processes, particularly in lipid and steroid/sterol metabolisms. Importantly, AR-V7 suppressed a tumor suppressor Claudin 7 expression, upregulated by c-MYC overexpression via the p53 signaling pathway. Claudin 7 overexpression significantly suppressed the c-MYC-driven HCC development under p53-deficient conditions. Our results suggest that the AR-V7 exacerbates the c-MYC-driven hepatocarcinogenesis by potentiating the oncogenic roles and minimizing the anti-oncogenic functions of c-MYC. Since AR-V7 is expressed in a subpopulation of HCC cases, it could contribute to the inter- and intra-heterogeneity of HCC.
RESUMEN
The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.
Asunto(s)
Proteínas de Ciclo Celular/genética , Cromosomas Humanos Y/genética , Gonadoblastoma/genética , Neoplasias Ováricas/genética , Neoplasias Testiculares/genética , Animales , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Ciclina B/metabolismo , Femenino , Gonadoblastoma/metabolismo , Gonadoblastoma/patología , Humanos , Masculino , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Seminoma/genética , Seminoma/metabolismo , Seminoma/patología , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologíaRESUMEN
BACKGROUND: Liver cancer is one of the major causes of cancer death worldwide, with significantly higher incidence and mortality among the male patients. Although sex hormones and their receptors could contribute to such sex differences, the story is incomplete. Genes on the male-specific region of the Y chromosome could play a role(s) in this cancer. TSPY is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY) that is ectopically expressed in a subset of male hepatocellular carcinomas (HCCs). Although various studies showed that TSPY expression is associated with poor prognosis in the patients and its overexpression promotes cell proliferation of various cancer cell lines, it remains unclear how TSPY contributes to the clinical outcomes of the HCC patients. Identifying the downstream genes and pathways of TSPY actions would provide novel insights on its contribution(s) to male predominance in this deadly cancer. RESULTS: To determine the effects of TSPY on HCC, a TSPY transgene was introduced to the HCC cell line, HuH-7, and studied with RNA-Seq transcriptome analysis. The results showed that TSPY upregulates various genes associated with cell-cycle and cell-viability, and suppresses cell-death related genes. To correlate the experimental observations with those of clinical specimens, transcriptomes of male HCCs with high TSPY expression were analyzed with reference to those with silent TSPY expression from the Cancer Genome Atlas (TCGA). The comparative analysis identified 49 genes, which showed parallel expression patterns between HuH-7 cells overexpressing TSPY and clinical specimens with high TSPY expression. Among these 49 genes, 16 likely downstream genes could be associated with survival rates in HCC patients. The major upregulated targets were cell-cycle related genes and growth factor receptor genes, including CDC25B and HMMR, whose expression levels are negatively correlated with the patient survival rates. In contrast, PPARGC1A, SLC25A25 and SOCS2 were downregulated with TSPY expression, and possess favorable prognoses for HCC patients. CONCLUSION: We demonstrate that TSPY could exacerbate the oncogenesis of HCC by differentially upregulate the expression of pro-oncogenic genes and downregulate those of anti-oncogenic genes in male HCC patients, thereby contributing to the male predominance in this deadly cancer.
RESUMEN
The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.
Asunto(s)
Carcinogénesis/genética , Proteínas de Ciclo Celular/genética , Cromosomas Humanos Y/genética , Proteínas de Unión al ADN/genética , Testículo/metabolismo , Humanos , Masculino , Proto-Oncogenes MasRESUMEN
TSPX is a tumor suppressor gene located at Xp11.22, a prostate cancer susceptibility locus. It is ubiquitously expressed in most tissues but frequently downregulated in various cancers, including lung, brain, liver and prostate cancers. The C-terminal acidic domain (CAD) of TSPX is crucial for the tumor suppressor functions, such as inhibition of cyclin B/CDK1 phosphorylation and androgen receptor transactivation. Currently, the exact role of the TSPX CAD in transcriptional regulation of downstream genes is still uncertain. Using different variants of TSPX, we showed that overexpression of either TSPX, that harbors a CAD, or a CAD-truncated variant (TSPX[∆C]) drastically retarded cell proliferation in a prostate cancer cell line LNCaP, but cell death was induced only by overexpression of TSPX. Transcriptome analyses showed that TSPX or TSPX[∆C] overexpression downregulated multiple cancer-drivers/oncogenes, including MYC and MYB, in a CAD-dependent manner and upregulated various tumor suppressors in a CAD-independent manner. Datamining of transcriptomes of prostate cancer specimens in the Cancer Genome Atlas (TCGA) dataset confirmed the negative correlation between the expression level of TSPX and those of MYC and MYB in clinical prostate cancer, thereby supporting the hypothesis that the CAD of TSPX plays an important role in suppression of cancer-drivers/oncogenes in prostatic oncogenesis.
RESUMEN
Testis-specific protein Y-encoded (TSPY) is the putative gene for the gonadoblastoma locus on the Y chromosome. TSPY is expressed in normal germ cells of fetal and adult testis and ectopically in tumor germ cells, including gonadoblastoma in intersex patients, testicular germ cell tumors, prostate cancer and other somatic cancers. It is a member of the TSPY/SET/NAP1 superfamily and harbors a highly conserved domain, termed SET/NAP domain. To explore its possible role(s) in tumorigenesis, we had performed a yeast two-hybrid screen of a fetal gonadal cDNA library and identified the translation elongation factor eEF1A as a binding partner for TSPY at the SET/NAP domain. TSPY and eEF1A were highly expressed and colocalized in tumor germ cells of human seminoma specimens, suggesting their possible interaction in germ cell tumors. They were colocalized in the cytoplasm and could be co-immunoprecipitated from transfected COS7 cells. Significantly, both eEF1A1 and eEF1A2 have postulated to be involved in various types of human cancer, including breast and prostate cancers. TSPY enhanced protein synthesis of a reporter gene, which was augmented by an overexpression of eEF1A. TSPY also increased the nuclear redistribution of eEF1A, resulting in a parallel increase in reporter gene transcripts. Our results suggest that TSPY could exert its oncogenic function(s) by interacting with eEF1As and stimulating gene expression via its enhancements in protein synthesis and gene transcription.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromosomas Humanos Y , Factor 1 de Elongación Peptídica/metabolismo , Animales , Secuencia de Bases , Células COS , Proteínas de Ciclo Celular/genética , Línea Celular , Chlorocebus aethiops , Cartilla de ADN , Dimerización , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/metabolismo , Unión Proteica , Espermatozoides/metabolismo , Testículo/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
Testicular germ cell tumours (TGCTs) are prevalent cancers among young men. Currently, there is no reliable animal model for TGCTs. To establish such animal models, we have explored the possibility of intratubular testicular transplantation as means to deliver tumour cells into the seminiferous tubules of host animals. Our results demonstrated that transplanted cells could effectively populate the testis of a recipient mouse and develop into TGCTs. In addition, the donor cells could be transfected with a specific transgene before transplantation, thereby providing an approach to evaluate the specific effects of gene functions in the oncogenic processes. Hence, depending on selection of specific donor cells or mixtures of donor cells, transplantation models of TGCTs could be significant for studies on the pathogenesis, diagnosis and therapies of such a prevalent and important cancer in men.
Asunto(s)
Modelos Animales , Trasplante de Neoplasias/métodos , Túbulos Seminíferos , Seminoma , Neoplasias Testiculares , Adulto , Animales , Biomarcadores de Tumor/análisis , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones DesnudosRESUMEN
Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single-cell embryos of the mouse. Pups with hSRY activated (hSRYON) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRYON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y-located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals.
Asunto(s)
Desarrollo Embrionario/genética , Genes Letales , Trastornos del Crecimiento/genética , Procesos de Determinación del Sexo/genética , Animales , Biomarcadores , Expresión Génica Ectópica , Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Marcación de Gen , Trastornos del Crecimiento/mortalidad , Humanos , Ratones , Ratones Transgénicos , Especificidad de Órganos/genética , Fenotipo , Proteína de la Región Y Determinante del Sexo/genética , Proteína de la Región Y Determinante del Sexo/metabolismo , Transducción de Señal , Transgenes , Cromosoma YRESUMEN
Testis specific protein Y-encoded (TSPY) is a Y-located proto-oncogene predominantly expressed in normal male germ cells and various types of germ cell tumor. Significantly, TSPY is frequently expressed in somatic cancers including liver cancer but not in adjacent normal tissues, suggesting that ectopic TSPY expression could be associated with oncogenesis in non-germ cell cancers. Various studies demonstrated that TSPY expression promotes growth and proliferation in cancer cells; however, its relationship to other oncogenic events in TSPY-positive cancers remains unknown. The present study seeks to correlate TSPY expression with other molecular features in clinical cancer samples, by analyses of RNA-seq transcriptome and DNA methylation data in the Cancer Genome Atlas (TCGA) database. A total of 53 genes, including oncogenic lineage protein 28 homolog B (LIN28B) gene and RNA-binding motif protein Y-linked (RBMY) gene, are identified to be consistently co-expressed with TSPY, and have been collectively designated as the TSPY co-expression network (TCN). TCN genes were simultaneously activated in subsets of liver hepatocellular carcinoma (30%) and lung adenocarcinoma (10%) regardless of pathological stage, but only minimally in other cancer types. Further analysis revealed that the DNA methylation level was globally lower in the TCN-active than TCN-silent cancers. The specific expression and methylation patterns of TCN genes suggest that they could be useful as biomarkers for the diagnosis, prognosis and clinical management of cancers, especially those for liver and lung cancers, associated with TSPY co-expression network genes.
Asunto(s)
Proteínas de Ciclo Celular/genética , Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Neoplasias/genética , Femenino , Genómica , Humanos , Masculino , Neoplasias/patología , Proto-Oncogenes MasRESUMEN
Male and female differ genetically by their respective sex chromosome composition, that is, XY as male and XX as female. Although both X and Y chromosomes evolved from the same ancestor pair of autosomes, the Y chromosome harbors male-specific genes, which play pivotal roles in male sex determination, germ cell differentiation, and masculinization of various tissues. Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development (previously termed as an intersex condition) with dysgenic gonads. Failure of gonadal development results not only in infertility, but also in increased risks of germ cell tumor (GCT), such as gonadoblastoma and various types of testicular GCT. Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers. These observations suggest that the Y-linked genes are involved in male health and diseases in more frequently than expected. Although only a small number of protein-coding genes are present in the male-specific region of Y chromosome, the impacts of Y chromosome genes on human diseases are still largely unknown, due to lack of in vivo models and differences between the Y chromosomes of human and rodents. In this review, we highlight the involvement of selected Y chromosome genes in cancer development in men.
Asunto(s)
Cromosomas Humanos Y/genética , Genes Ligados a Y/fisiología , Neoplasias/genética , Neoplasias/fisiopatología , Azoospermia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Genes Ligados a Y/genética , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/fisiopatología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/fisiologíaRESUMEN
BACKGROUND: The human TSPY is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY). Various molecular, pathological and transgenic mouse studies suggest that TSPY is a Y-located proto-oncogene contributing to the initiation/progression in human cancers, including germ cell tumors and various somatic cancers, such as prostate and liver cancer, and melanoma. The TgTSPY9 transgenic mouse line harbors a 8.2-kb human TSPY structural gene, which is tandemly integrated in the mouse Y chromosome, and expressed in a similar pattern as that of the endogenous gene in the human genome. This mouse model of human TSPY gene offers an opportunity to examine its behavior and potential contribution in various mouse models of human diseases, such as human cancers. We had investigated the expression of such TSPY-transgene in the LADY mouse model of prostate cancer, harboring a SV40 T antigen gene directed by a rat probasin promoter; and compared the expression pattern with those of endogenous TSPY gene and biomarkers in human prostate cancer specimens. RESULTS: By introducing the Y-located TSPY-transgene to the LADY mice, we had examined the expression pattern of the human TSPY during prostatic oncogenesis in this mouse model of prostate cancer. Our results showed that the TSPY-transgene was activated in selected areas of the hypercellular stroma but not in the intraepithelial cells/neoplasia in the prostates of TgTSPY9/LADY mice. Using a specific biomarker, FOXA1, for epithelial cells, we demonstrated that TSPY-positive cells proliferated exclusively in the cancerous stroma in the LADY model at late stages of tumorigenesis. In contrast, in the human situation, TSPY was predominantly co-expressed with FOXA1 in the epithelial cells of PIN lesions and FOXA1 and another cancer biomarker, AMACR, in the adenocarcinoma cells in clinical prostate cancer samples of various degrees of malignancy. CONCLUSIONS: Our data show that human TSPY could be abnormally activated during prostatic oncogenesis, and could possibly contribute to the heterogeneity of prostate cancer. The differential expression patterns of the human TSPY between the LADY mouse model and clinical prostate cancer suggest potential limitations of current mouse models for studies of either TSPY behavior in diseased conditions or prostate cancer development.
RESUMEN
There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Colangiocarcinoma/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proteínas de Ciclo Celular/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Proteínas de Unión al ADN , Femenino , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Glipicanos/genética , Glipicanos/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Isoformas de Proteínas , Análisis de Secuencia de ADN , Factores Sexuales , Análisis de Matrices TisularesRESUMEN
The gonadoblastoma locus on the human Y chromosome (GBY) is postulated to serve normal functions in spermatogenesis, but could exert oncogenic properties in predisposing susceptible germ cells to tumorigenesis in incompatible niches such as streaked gonads in XY sex reversed patients or dysfunctional testis in males. The testis-specific protein Y-linked (TSPY) repeat gene has recently been demonstrated to be the putative gene for GBY, based on its location on the GBY critical region, expression patterns in early and late stages of gonadoblastoma and ability to induce gonadoblastoma-like structures in the ovaries of transgenic female mice. Over-expression of TSPY accelerates G(2)/M progression in the cell cycle by enhancing the mitotic cyclin B-CDK1 kinase activities. Currently the normal functions of TSPY in spermatogenesis are uncertain. Expression studies of TSPY, and its X-homologue, TSPX, in normal human testis suggest that TSPY is co-expressed with cyclin B1 in spermatogonia and various stages of spermatocytes while TSPX is principally expressed in Sertoli cells in the human testis. The co-expression pattern of TSPY and cyclin B1 in spermatogonia and spermatocytes suggest respectively that 1) TSPY is important for male spermatogonial cell replication and renewal in the testis; and 2) TSPY could be a catalyst/meiotic factor essential for augmenting the activities of cyclin B-cyclin dependent kinases, important for the differentiation of the spermatocytes in prophase I and in preparation for consecutive rounds of meiotic divisions without an intermediate interphase during spermatogenesis.
Asunto(s)
Proteínas de Ciclo Celular/genética , Cromosomas Humanos Y/genética , Gonadoblastoma/genética , Espermatogénesis/genética , Animales , Proteína Quinasa CDC2/metabolismo , Células COS , Proteínas de Ciclo Celular/fisiología , Chlorocebus aethiops , Ciclina B1/genética , Ciclina B1/metabolismo , Proteínas de Unión al ADN , Femenino , Humanos , Masculino , Proteínas NuclearesRESUMEN
Hepatitis B virus (HBV) infection is a major risk for hepatocellular carcinoma (HCC), and it is a serious global health problem with two billion people exposed to it worldwide. HBx, an essential factor for viral replication and a putative oncoprotein encoded by the HBV genome, has been shown to promote oncogenic properties at multiple sites in HBV-infected liver cells. The expression level of HBx closely associates with the development and progression of HCC, therefore the mechanism(s) regulating the stability of HBx is important in oncogenesis of HBV-infected cells. We demonstrate that the X-linked tumor suppressor TSPX enhances the degradation of HBx through the ubiquitin-proteasome pathway. TSPX interacts with both HBx and a proteasome 19S lid subunit RPN3 via its C-terminal acidic tail. Most importantly, over-expression of RPN3 protects HBx from, and hence acts as a negative regulator for, proteasome-dependent degradation. TSPX abrogates the RPN3-depedent stabilization of HBx, suggesting that TSPX and RPN3 act competitively in regulation of HBx stability. Since mutation and/or epigenetic repression of X-located tumor suppressor gene(s) could significantly predispose males to human cancers, our data suggest that TSPX-induced HBx degradation could play key role(s) in hepatocarcinogenesis among HBV-infected HCC patients.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Transactivadores/metabolismo , Ubiquitina/metabolismo , Western Blotting , Carcinoma Hepatocelular/genética , Células Cultivadas , Proteínas de Unión al ADN , Humanos , Riñón/citología , Riñón/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Procesamiento Proteico-Postraduccional , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
The testis specific protein Y-encoded (TSPY) is a member of TSPY/SET/NAP1 superfamily, encoded within the gonadoblastoma locus on the Y chromosome. TSPY shares a highly conserved SET/NAP-domain responsible for protein--protein interaction among TSPY/SET/NAP1 proteins. Accumulating data, so far, support the role of TSPY as the gonadoblastoma gene, involved in germ cell tumorigenesis. The X-chromosome homolog of TSPY, TSPX is expressed in various tissues at both fetal and adult stages, including the brain, and is capable of interacting with the multi-domain adapter protein CASK, thereby influencing the synaptic and transcriptional functions and developmental regulation of CASK in the brain and other neural tissues. Similar to TSPX, we demonstrated that TSPY could interact with CASK at its SET/NAP-domain in cultured cells. Transgenic mice harboring a human TSPY gene and flanking sequences showed specific expression of the human TSPY transgene in both testis and brain. The neural expression pattern of the human TSPY gene overlapped with those of the endogenous mouse Cask and Tspx gene. Similarly with TSPX, TSPY was co-localized with CASK in neuronal axon fibers in the brain, suggesting a potential role(s) of TSPY in development and/or physiology of the nervous system.