RESUMO
Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.
Assuntos
Fígado Gorduroso , Hepatopatia Gordurosa não Alcoólica , Animais , Feminino , Humanos , Masculino , Camundongos , Dieta Hiperlipídica/efeitos adversos , Estrogênios , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Expressão Gênica , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/uso terapêutico , Fatores de Transcrição de Domínio TEARESUMO
BACKGROUND: Estrogen receptor beta (ERß, Esr2) plays a pivotal role in folliculogenesis and ovulation, yet its exact mechanism of action is mainly uncharacterized. RESULTS: We here performed ERß ChIP-sequencing of mouse ovaries followed by complementary RNA-sequencing of wild-type and ERß knockout ovaries. By integrating the ERß cistrome and transcriptome, we identified its direct target genes and enriched biological functions in the ovary. This demonstrated its strong impact on genes regulating organism development, cell migration, lipid metabolism, response to hypoxia, and response to estrogen. Cell-type deconvolution analysis of the bulk RNA-seq data revealed a decrease in luteal cells and an increased proportion of theca cells and a specific type of cumulus cells upon ERß loss. Moreover, we identified a significant overlap with the gene regulatory network of liver receptor homolog 1 (LRH-1, Nr5a2) and showed that ERß and LRH-1 extensively bound to the same chromatin locations in granulosa cells. Using ChIP-reChIP, we corroborated simultaneous ERß and LRH-1 co-binding at the ERß-repressed gene Greb1 but not at the ERß-upregulated genes Cyp11a1 and Fkbp5. Transactivation assay experimentation further showed that ERß and LRH-1 can inhibit their respective transcriptional activity at classical response elements. CONCLUSIONS: By characterizing the genome-wide endogenous ERß chromatin binding, gene regulations, and extensive crosstalk between ERß and LRH-1, along with experimental corroborations, our data offer genome-wide mechanistic underpinnings of ovarian physiology and fertility.
Assuntos
Receptor beta de Estrogênio , Ovário , Animais , Feminino , Camundongos , Cromatina/genética , Receptor beta de Estrogênio/genética , Regulação da Expressão Gênica , TranscriptomaRESUMO
Estrogen, through the regulation of cytokine production, can act both as pro-inflammatory and anti-inflammatory signals dependent on the tissue context. In breast cancer cells, ERα is known to modulate inflammatory signaling through interaction with NFκB. Whether ERß has a role in inflammation is less explored. Low levels of ERß have been corroborated in several immune-related organs and, for example, in colonic epithelial cells. Specifically, an impact of ERß on colitis and colitis-associated colorectal cancer (CRC) is experimentally supported, using ERß-selective agonists, full-body ERß knockout mice and, most recently, intestinal epithelial-specific knockout mice. An intricate crosstalk between ERß and TNFα/NFκB signaling in the colon is supported, and ERß activation appears to reduce macrophage infiltration also during high fat diet (HFD)-induced colon inflammation. Finally, the gut microbiota plays a fundamental role in the pathogenesis of colitis and ERß has been indicated to modulate the microbiota diversity during colitis and colitis-induced CRC. ERß is thus proposed to protect against colitis, by modulating NFκB signaling, immune cell infiltration, and/or microbiota composition. Selective activation of ERß may therefore constitute a suitable preventative approach for the treatment of for example colitis-associated CRC.
Assuntos
Colite , Receptor beta de Estrogênio , Animais , Colite/patologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio/genética , Estrogênios , Inflamação/patologia , Camundongos , Camundongos Knockout , Fator de Necrose Tumoral alfaRESUMO
There are significant sex differences in colorectal cancer (CRC), including in incidence, onset, and molecular characteristics. Further, while inflammatory bowel disease (IBD) is a risk factor for CRC in both sexes, men with IBD have a 60% higher risk of developing CRC compared to women. In this study, we investigated sex differences during colitis-associated CRC (CAC) using a chemically induced CAC mouse model. The mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) and followed for 9 and 15 weeks. We performed RNA-sequencing of colon samples from males (n = 15) and females (n = 15) to study different stages of inflammation and identify corresponding transcriptomic sex differences in non-tumor colon tissue. We found a significant transcriptome response to AOM/DSS treatment in both sexes, including in pathways related to inflammation and cell proliferation. Notably, we found a stronger response in males and that male-specific differentially expressed genes were involved in NFκB signaling and circadian rhythm. Further, an overrepresented proportion of male-specific gene regulations were predicted to be targets of Stat3, whereas for females, targets of the glucocorticoid receptor (Gr/Nr3c1) were overrepresented. At 15 weeks, the most apparent sex difference involved genes with functions in T cell proliferation, followed by the regulation of demethylases. The majority of sex differences were thus related to inflammation and the immune system. Our novel data, profiling the transcriptomic response to chemically induced colitis and CAC, indicate clear sex differences in CRC initiation and progression.
Assuntos
Colite , Neoplasias Colorretais , Doenças Inflamatórias Intestinais , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Colite/genética , Neoplasias Colorretais/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/complicações , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA , Receptores de Glucocorticoides/genética , TranscriptomaRESUMO
Colorectal cancer (CRC) is the third leading cause of cancer death in the western world. In women, menopausal hormone therapy has been shown to reduce CRC incidence by 20%. Studies demonstrate that estrogen activating estrogen receptor beta (ERß) protects against CRC. ERß is a nuclear receptor that regulates gene expression through interactions with the chromatin. This molecular mechanism is, however, not well characterized in colon. Here, we present for the first time, the cistrome of ERß in different colon cancer cell lines. We use cell lines engineered to express ERß, optimize and validate an ERß antibody for chromatin-immunoprecipitation (ChIP), and perform ChIP-Seq. We identify key binding motifs, including ERE, AP-1, and TCF sites, and we determine enrichment of binding to cis-regulatory chromatin sites of genes involved in tumor development, cell migration, cell adhesion, apoptosis, and Wnt signaling pathways. We compare the corresponding cistromes of colon and breast cancer and find that they are conserved for about a third of genes, including GREB1, but that ERß tethering to TCF and KLF family motifs is characteristic for colon. We exemplify upregulation of putative CRC tumor suppressor gene CST5 where ERß in colon cells binds to cis-regulatory regions nearby (-351 bp) the transcriptional start site. Our work provides a foundation for understanding the mechanism of action of ERß in CRC prevention.
Assuntos
Biomarcadores Tumorais/metabolismo , Cromatina/metabolismo , Neoplasias do Colo/patologia , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Genoma Humano , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular , Movimento Celular , Proliferação de Células , Cromatina/genética , Imunoprecipitação da Cromatina , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Células Tumorais CultivadasRESUMO
BACKGROUND: Menopausal hormone therapy (MHT) reduces the risk of developing colorectal cancer (CRC), yet it is largely unclear whether it could also influence survival in women with CRC. Therefore, we aimed to investigate the influence of prediagnostic MHT use on CRC-specific and all-cause mortality in women with CRC. METHODS: This nationwide nested cohort study, within a large population-based matched cohort, included all women diagnosed with incident CRC between January 2006 and December 2012 (N = 7814). A total of 1529 women had received at least one dispensed prescription of systemic MHT before CRC diagnosis, and 6285 CRC women with CRC did not receive MHT during the study period, as ascertained from the Swedish Prescribed Drug Registry. Multivariable Cox regression models provided adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for CRC-specific mortality and all-cause mortality. RESULTS: Past use of prediagnostic estrogen-only therapy (E-MHT) was associated with lower CRC-specific (HR = 0.67, 95%CI 0.44-0.99) and all-cause mortality (HR = 0.68, 95%CI 0.59-0.93). However, all-cause mortality (HR = 1.23, 95%CI 1.02-1.48) was elevated among current prediagnostic E-MHT users who were 70+ years at diagnosis. Current estrogen combined progestin therapy (EP-MHT) was associated with higher CRC-specific mortality (HR = 1.61, 95%CI 1.06-2.44) in older women, but no association was shown for all-cause mortality. CONCLUSIONS: Our findings suggest that E-MHT, but not EP-MHT use, might be associated with improved CRC survival, indicating a potential role of estrogens in sex hormone-related cancers. However, association of MHT use with grade of cancer remains unclear.
Assuntos
Neoplasias Colorretais , Menopausa , Idoso , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Feminino , Humanos , Suécia/epidemiologiaRESUMO
Colorectal cancer (CRC) is the third leading cause of cancer deaths. Advances within bioinformatics, such as machine learning, can improve biomarker discovery and ultimately improve CRC survival rates. There are clear sex differences in CRC characteristics, but the impact of sex has not been considered with regards to CRC biomarkers. Our aim here was to investigate sex differences in the transcriptome of a normal colon and CRC, and between paired normal and tumor tissue. Next, we attempted to identify CRC diagnostic and prognostic biomarkers and investigate if they are sex-specific. We collected paired normal and tumor tissue, performed RNA-seq, and applied feature selection in combination with machine learning to identify the top CRC diagnostic biomarkers. We used The Cancer Genome Atlas (TCGA) data to identify sex-specific CRC diagnostic biomarkers and performed an overall survival analysis to identify sex-specific prognostic biomarkers. We found transcriptomic sex differences in both the normal colon tissue and in CRC. Forty-four of the top-ranked biomarkers were sex-specific and 20 biomarkers showed a sex-specific prognostic value. Our data show the importance of sex in the discovery of CRC biomarkers. We propose 20 sex-specific CRC prognostic biomarkers, including ESM1, GUCA2A, and VWA2 for males and CLDN1 and FUT1 for females.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Feminino , Genômica , Humanos , Aprendizado de Máquina , Masculino , Prognóstico , Fatores Sexuais , Análise de SobrevidaRESUMO
OBJECTIVES: To examine long-term participation and dropout rates in Australian youth swimming using survival analyses and to determine whether multiple individual, socio-demographic, and competition-related factors influenced dropout. DESIGN: Retrospective cohort study of registration and competitive performance data. METHODS: Part 1-Registration data from N = 17 161 female (n = 9400) and male (n = 7761) New South Wales (NSW) swimmers aged 10-15 years (inclusive). Part 2-Competition level involvement in a subsample of female (n = 1011) and male (n = 811) swimmers, aged 12-15 years, was also examined. To determine dropout rates and influential factors, Kaplan-Meier survival analyses supplemented by Cox regression were used. RESULTS: (1) Kaplan-Meier analyses identified median sustained participation rates of four years (95% CI = 3.93-4.06), with 15.9% maintaining participation over 10 years. Cox regressions identified age-group was associated with dropout (P < .001), with a 184.9% higher Hazard Rate (HR) for 10- vs 15-year-olds. Residential proximity to major cities was associated with dropout (P < .001), with urban swimmers reporting a 24.8% higher HR rate than rural swimmers. Sex and relative age were not associated with dropout. (2) The subsample median sustained participation was five years (95% CI = 4.79-5.20), with 25.3% maintaining participation for ten years. Level of competition was associated (P < .001), with an 86% higher HR when considering lower competition levels (ie, club/district v national). CONCLUSION: In a large representative sample of swimmers, survival analyses identified age-group, competition level, and city proximity were associated with increased swimming dropout rates.
Assuntos
Comportamento Competitivo , Natação/psicologia , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , New South Wales , Modelos de Riscos Proporcionais , Estudos Retrospectivos , População Rural , Fatores Sexuais , Participação Social , Fatores Socioeconômicos , População UrbanaRESUMO
miR-206 is known to suppress breast cancer. However, while it is expressed in mammary stem cells, its function in such nontumor cells is not well understood. Here, we explore the role of miR-206 in undifferentiated, stem-like mammary cells using the murine mammary differentiation model HC11, genome-wide gene expression analysis, and functional assays. We describe the miR-206-regulated gene landscape and propose a network whereby miR-206 suppresses tumor development. We functionally demonstrate that miR-206 in nontumor stem-like cells induces a G1-S cell cycle arrest, and reduces colony formation and epithelial-to-mesenchymal transition markers. Finally, we show that addition of miR-206 accelerates the mammary differentiation process along with related accumulation of lipids. We conclude that miR-206 impacts a network of signaling pathways, and acts as a regulator of proliferation, stemness, and mammary cell differentiation in nontumor stem-like mammary cells. Our study provides a broad insight into the breast cancer suppressive functions of miR-206.
Assuntos
Diferenciação Celular/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Humanas/citologia , MicroRNAs/metabolismo , Animais , Biomarcadores/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Fase G1/genética , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Lipídeos , Camundongos , MicroRNAs/genética , Fase S/genética , Células-Tronco/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima/genéticaRESUMO
Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone-replacement therapy reduces CRC incidences, and the estrogen receptor beta (ERß/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERß impacts the gut microbiota. Mice with and without intestine-specific deletion of ERß (ERßKOVil ) were generated using the Cre-LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples (N = 39). Differences in the microbiota due to AOM/DSS and absence of ERß were identified through bioinformatic analyses of the 16S-Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis-induced CRC reduced the gut microbiota diversity and that loss of ERß enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5-fold, p = 0.004), and this was enhanced in females and in ERßKOVil mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERß in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERß contributes to a more favorable microbiome that could attenuate CRC development.
Assuntos
Colite/metabolismo , Colite/microbiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Receptor beta de Estrogênio/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Azoximetano/farmacologia , Sulfato de Dextrana/farmacologia , Receptor beta de Estrogênio/deficiência , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: Sex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers. METHODS: We analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012. RESULTS: We found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant. CONCLUSIONS: Sexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.
Assuntos
Neoplasias/epidemiologia , Fatores Sexuais , Feminino , Saúde Global , História do Século XX , História do Século XXI , Humanos , Incidência , Masculino , Neoplasias/história , Vigilância da População , Programa de SEER , Suécia , Estados UnidosRESUMO
Estrogen receptors are expressed and their cognate ligands produced in all vertebrates, indicative of important and conserved functions. Through evolution estrogen has been involved in controlling reproduction, affecting both the development of reproductive organs and reproductive behavior. This review broadly describes the synthesis of estrogens and the expression patterns of aromatase and the estrogen receptors, in relation to estrogen functions in the developing fetus and child. We focus on the role of estrogens for the development of reproductive tissues, as well as non-reproductive effects on the developing brain. We collate data from human, rodent, bird and fish studies and highlight common and species-specific effects of estrogen signaling on fetal development. Morphological malformations originating from perturbed estrogen signaling in estrogen receptor and aromatase knockout mice are discussed, as well as the clinical manifestations of rare estrogen receptor alpha and aromatase gene mutations in humans. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
Assuntos
Desenvolvimento Embrionário/fisiologia , Receptores de Estrogênio/fisiologia , Animais , Aves/embriologia , Aves/genética , Criança , Desenvolvimento Embrionário/genética , Feminino , Peixes/embriologia , Peixes/genética , Hormônios/biossíntese , Humanos , Camundongos , Camundongos Knockout , Transdução de Sinais/genéticaRESUMO
Triple-negative breast cancer (TNBC) is characterized by aggressiveness and affects 10-20% of breast cancer patients. Since TNBC lacks expression of ERα, PR and HER2, existing targeted treatments are not effective and the survival is poor. In this study, we demonstrate that the tumor suppressor microRNA miR-200a directly regulates the oncogene EPH receptor A2 (EPHA2) and modulates TNBC migration. We show that EPHA2 expression is correlated with poor survival specifically in basal-like breast cancer and that its expression is repressed by miR-200a through direct interaction with the 3'UTR of EPHA2. This regulation subsequently affects the downstream activation of AMP-activated protein kinase (AMPK) and results in decreased cell migration of TNBC. We establish that miR-200a directs cell migration in a dual manner; in addition to regulating the well-characterized E-cadherin pathway it also regulates a EPHA2 pathway. The miR-200a-EPHA2 axis is a novel mechanism highlighting the possibility of utilizing miR-200a delivery to target TNBC metastases.
Assuntos
MicroRNAs/genética , Receptor EphA2/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/patologia , Regiões 3' não Traduzidas/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ativação Enzimática/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Receptor EphA2/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
This work combined gene and protein expression, gas chromatography-flame ionization detector, and hydrophilic interaction liquid chromatography-tandem mass spectrometry to compare lipid metabolism changes in undifferentiated/proliferating vs. functionally differentiated mammary epithelial cells (MECs) and to study their correlation to breast cancer survival. Sixty-eight genes involved in lipid metabolism were changed in MEC differentiation. Differentiated cells showed induction of Elovl6 (2-fold), Scd1 (4-fold), and Fads2 (2-fold), which correlated with increased levels of C16:1 n-7 and C18:1 n-9 (1.5-fold), C20:3 n-6 (2.5-fold), and C20:4 n-6 (6-fold) fatty acids (FAs) and more phospholipids (PLs) containing these species. Further, increased expression (2- to 3-fold) of genes in phosphatidylethanolamine (PE) de novo biosynthesis resulted in a 20% PE increase. Proliferating/undifferentiated cells showed higher C16:0 (1.7-fold) and C18:2 n-6 (4.2-fold) levels and more PLs containing C16:0 FAs [PC(16:0/16:1), PG(16:0/18:2), PG(16:0/18:1), and SM(16:0/18:0)]. Kaplan-Meier analysis of data from 3455 patients with breast cancer disclosed a positive correlation for 59% of genes expressed in differentiated MECs with better survival. PE biosynthesis and FA oxidation correlated with better prognosis in patients with breast cancer, including the basal-like subtype. Therefore, genes involved in mammary gland FA and PL metabolism and their resulting molecular species reflect the cellular proliferative ability and differentiation state and deserve further studies as potential markers of breast cancer progression
Assuntos
Neoplasias da Mama/metabolismo , Diferenciação Celular , Células Epiteliais/metabolismo , Ácidos Graxos/biossíntese , Regulação Neoplásica da Expressão Gênica , Fosfolipídeos/biossíntese , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Neoplasias da Mama/diagnóstico , Linhagem Celular Tumoral , Células Epiteliais/citologia , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos , Ácidos Graxos/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosfolipídeos/genética , Prognóstico , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismoRESUMO
Estrogen drives the growth of some cancers, such as breast cancer, via estrogen receptor alpha (ERα). Estrogen also activates ERß, but whether ERß is expressed and has a role in different cancers is debated. The use of nonspecific antibodies has contributed to the confusion, and this review delves into ERß's controversial role in cancer and focuses on tumor expression that can be supported by non-antibody-dependent assays. We discuss its expression at the transcript level and focus on its potential role in lymphoma, granulosa cell tumors, testicular, and adrenal cancers, emphasizing recent findings and the complexities that necessitate further research.
Assuntos
Receptor beta de Estrogênio , Neoplasias , Humanos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Neoplasias/metabolismo , Neoplasias/genética , Feminino , Animais , Masculino , Regulação Neoplásica da Expressão Gênica , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Tumor de Células da Granulosa/metabolismo , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Linfoma/metabolismo , Linfoma/genética , Linfoma/patologiaRESUMO
Human adenovirus (HAdV) type F41 has been identified as a possible cause of the non-A-to-E hepatitis outbreak. This study uses wastewater monitoring to track HAdV F40 and F41, supporting clinical investigations and providing insights into the pathogen's role in the outbreak. Given the limited clinical monitoring in Sweden of HAdV-F40/41, this approach also helps estimate the true infection burden of this pathogen during the outbreak. This study developed three qPCR assays for the hexon, penton, and fiber genes of HAdV F40 and F41. The hexon assay was F41-specific, while the fiber assay detected multiple HAdV-F strains. Comprehensive monitoring of HAdV-F40/41 levels in Stockholm's wastewater was conducted over 1.5 years, capturing the period before, during, and after the outbreak. A significant infection wave was observed in spring 2022, with strains beyond lineage 2 contributing to the outbreak. Moreover, simultaneous SARS-CoV-2 surveillance revealed that HAdV-F infections peaked at different times from COVID-19, but the HAdV-F wave aligned with the relaxation of pandemic restrictions. These findings offer valuable insights for future HAdV-F investigations and confirm its role in the non-A-to-E hepatitis outbreak.
RESUMO
There is epidemiological, animal and in vitro evidence that estrogen receptor ß (ERß) can mediate protective effects against colon cancer, but the mechanism is not completely understood. Previous research has indicated critical pathways whereby ERß acts in an antitumorigenic fashion. In this study, we investigate ERß's impact on the microRNA (miRNA) pool in colon cancer cells using large-scale genomic approaches, bioinformatics and focused functional studies. We detect and confirm 27 miRNAs to be significantly changed following ERß expression in SW480 colon cancer cells. Among these, the oncogenic miR-17-92 cluster and miR-200a/b are strongly downregulated. Using target prediction and anticorrelation to gene expression data followed by focused mechanistic studies, we demonstrate that repression of miR-17 is a secondary event following ERß's downregulatory effect on MYC. We show that re-introduction of miR-17 can reverse the antiproliferative effects of ERß. The repression of miR-17 also influences cell death upon DNA damage and mediates regulation of NCOA3 (SRC-3) and CLU in colon cancer cells. We further determine that the downregulation of miR-200a/b mediates increased ZEB1 while decreasing E-cadherin levels in ERß-expressing colon cancer cells. Changes in these genes correspond to significant alterations in morphology and migration. Our work contributes novel data of ERß and miRNA in the colon. Elucidating the mechanism of ERß and biomarkers of its activity has significant potential to impact colon cancer prevention and treatment.
Assuntos
Neoplasias do Colo/genética , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/genética , Caderinas/metabolismo , Morte Celular , Movimento Celular , Forma Celular , Neoplasias do Colo/metabolismo , Biologia Computacional/métodos , Regulação para Baixo , Transição Epitelial-Mesenquimal , Receptor beta de Estrogênio/genética , Perfilação da Expressão Gênica , Células HT29 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , MicroRNAs/genética , Coativador 3 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/metabolismo , RNA Neoplásico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
INTRODUCTION: Liver × receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Published reports of anti-proliferative effects of synthetic LXR ligands on breast, prostate, ovarian, lung, skin, and colorectal cancer cells suggest that LXRs are potential targets in cancer prevention and treatment. METHODS: To further determine the effects of LXR ligands and identify their potential mechanisms of action in breast cancer cells, we carried out microarray analysis of gene expression in four breast cancer cell lines following treatments with the synthetic LXR ligand GW3965. Differentially expressed genes were further subjected to gene ontology and pathway analyses, and their expression profiles and associations with disease parameters and outcomes were examined in clinical samples. Response of E2F target genes were validated by real-time PCR, and the posited role of E2F2 in breast cancer cell proliferation was tested by RNA interference experiments. RESULTS: We observed cell line-specific transcriptional responses as well as a set of common responsive genes. In the common responsive gene set, upregulated genes tend to function in the known metabolic effects of LXR ligands and LXRs whereas the downregulated genes mostly include those which function in cell cycle regulation, DNA replication, and other cell proliferation-related processes. Transcription factor binding site analysis of the downregulated genes revealed an enrichment of E2F binding site sequence motifs. Correspondingly, E2F2 transcript levels are downregulated following LXR ligand treatment. Knockdown of E2F2 expression, similar to LXR ligand treatment, resulted in a significant disruption of estrogen receptor positive breast cancer cell proliferation. Ligand treatment also decreased E2F2 binding to cis-regulatory regions of target genes. Hierarchical clustering of breast cancer patients based on the expression profiles of the commonly downregulated LXR ligand-responsive genes showed a strong association of these genes with patient survival. CONCLUSIONS: Taken together, these results indicate that LXR ligands target gene networks, including those regulated by E2F family members, are critical for tumor biology and disease progression and merit further consideration as potential agents in the prevention and treatment of breast cancers.
Assuntos
Benzoatos/metabolismo , Benzilaminas/metabolismo , Neoplasias da Mama/genética , Fator de Transcrição E2F2/biossíntese , Receptores Nucleares Órfãos/metabolismo , Benzoatos/administração & dosagem , Benzilaminas/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Transcrição E2F2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Receptores X do Fígado , Regiões Promotoras Genéticas , Transcrição Gênica/efeitos dos fármacosRESUMO
An approach based on wastewater epidemiology can be used to monitor the COVID-19 pandemic by assessing the gene copy number of SARS-CoV-2 in wastewater. In the present study, we statistically analyzed such data from six inlets of three wastewater treatment plants, covering six regions of Stockholm, Sweden, collected over an approximate year period (week 16 of 2020 to week 22 of 2021). SARS-CoV-2 gene copy number and population-based biomarker PMMoV, as well as clinical data, such as the number of positive cases, intensive care unit numbers, and deaths, were analyzed statistically using correlations and principal component analysis (PCA). Despite the population differences, the PCA for the Stockholm dataset showed that the case numbers are well grouped across wastewater treatment plants. Furthermore, when considering the data from the whole of Stockholm, the wastewater characteristics (flow rate m3/day, PMMoV Ct value, and SARS-CoV gene copy number) were significantly correlated with the public health agency's report of SARS-CoV-2 infection rates (0.419 to 0.95, p-value < 0.01). However, while the PCA results showed that the case numbers for each wastewater treatment plant were well grouped concerning PC1 (37.3%) and PC2 (19.67%), the results from the correlation analysis for the individual wastewater treatment plants showed varied trends. SARS-CoV-2 fluctuations can be accurately predicted through statistical analyses of wastewater-based epidemiology, as demonstrated in this study.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Suécia , Águas Residuárias , Pandemias , RNA ViralRESUMO
Granulosa cell tumors (GCTs) are rare ovarian tumors comprising an adult and a juvenile subtype. They have a generally good prognosis, but the survival rate drastically declines in patients with late-stage or recurring tumors. Due to the rarity of GCTs, the tumor type is largely understudied and lacks a specific treatment strategy. Estrogen receptor beta (ERß/ESR2) has been found to be highly expressed in GCTs, which could be of therapeutic importance since it can be targeted with small molecules. However, its role in GCTs is not known. In this review, we summarize the current knowledge about the action of ERß in the ovary and discuss its prospective role in GCTs.