RESUMO
Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Viroses/patologia , Adulto , Idoso , Área Sob a Curva , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Curva ROC , Fatores de Risco , Viroses/complicações , Adulto Jovem , alfa-Fetoproteínas/análiseRESUMO
Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Ductal Pancreático , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM , Neoplasias Pancreáticas , Proteínas com Domínio LIM/metabolismo , Proteínas com Domínio LIM/genética , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Masculino , Feminino , Movimento Celular , Linhagem Celular Tumoral , Prognóstico , Pessoa de Meia-IdadeRESUMO
Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2 and LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2 and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of the mitogen-activated protein kinase-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.
Assuntos
Carcinoma Ductal Pancreático , Glucose , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Neoplasias Pancreáticas , Fator de Transcrição AP-1 , Humanos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Animais , Camundongos , Glucose/metabolismo , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases , Regulação Neoplásica da Expressão Gênica , Hexoquinase/metabolismo , Hexoquinase/genética , Proliferação de Células , Transdução de Sinais , Reprogramação MetabólicaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.
Assuntos
Carcinoma Ductal Pancreático , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Masculino , Feminino , Metaboloma , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Invasividade Neoplásica , Transcriptoma , Pessoa de Meia-Idade , Reprogramação MetabólicaRESUMO
Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.
Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Herança Multifatorial/genética , Receptores de Estrogênio/genética , Fatores de RiscoRESUMO
BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.
Assuntos
Hiperplasia Prostática , Neoplasias da Próstata , Humanos , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Sequenciamento do Exoma , Qualidade de Vida , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Próstata/patologia , Dineínas do Axonema/genética , Fatores de Elongação da Transcrição/genética , Cinesinas/genéticaRESUMO
Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
Assuntos
População Negra/genética , Estatura/genética , Estudo de Associação Genômica Ampla , África/etnologia , Negro ou Afro-Americano/genética , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Characterization of the breast cancer (BC) immune response may provide information for a point of intervention, such as application of immunotherapeutic treatments. In this study, we sought to recover and characterize the adaptive immune receptor (IR) recombination reads from genomics files representing Kenyan patients, to better understand the immune response specifically related to those patients. METHODS: We used a previously applied algorithm and software to obtain productive IR recombination reads from cancer and adjacent normal tissue samples representing 22 Kenyan BC patients. RESULTS: From both the RNAseq and exome files, there were significantly more T-cell receptor (TCR) recombination reads recovered from tumor samples compared to marginal tissue samples. Also, the immunoglobulin (IG) genes were expressed at a much higher level than the TCR genes (p-value = 0.0183) in the tumor samples. And, the tumor IG CDR3s consistently represented more positively charged amino acid R-groups, in comparison to the marginal tissue, IG CDR3s. CONCLUSION: For Kenyan patients, a high level of IG expression, representing specific CDR3 chemistries, was associated with BC. These results lay the foundation for studies that could support specific immunotherapeutic interventions for Kenyan BC patients.
Assuntos
Neoplasias da Mama , Linfócitos T , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Quênia/epidemiologia , Genes de Imunoglobulinas , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Low socioeconomic status (SES) is associated with early onset of chronic diseases and reduced life expectancy. The involvement of neighborhood-level factors in defining cancer risk and outcomes for marginalized communities has been an active area of research for decades. Yet, the biological processes that underlie the impact of SES on chronic health conditions, such as cancer, remain poorly understood. To date, limited studies have shown that chronic life stress is more prevalent in low SES communities and can affect important molecular processes implicated in tumor biology such as DNA methylation, inflammation, and immune response. Further efforts to elucidate how neighborhood-level factors function physiologically to worsen cancer outcomes for disadvantaged communities are underway. This review provides an overview of the current literature on how socioenvironmental factors within neighborhoods contribute to more aggressive tumor biology, specifically in Black U.S. women and men, including the impact of environmental pollutants, neighborhood deprivation, social isolation, structural racism, and discrimination. We also summarize commonly used methods to measure deprivation, discrimination, and structural racism at the neighborhood-level in cancer health disparities research. Finally, we offer recommendations to adopt a multi-faceted intersectional approach to reduce cancer health disparities and develop effective interventions to promote health equity.
Assuntos
Negro ou Afro-Americano , Neoplasias , Feminino , Humanos , Masculino , Doença Crônica , Promoção da Saúde , Neoplasias/epidemiologia , Neoplasias/etiologia , Características de Residência , Classe Social , Fatores SocioeconômicosRESUMO
BACKGROUND: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized. METHODS: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model. RESULTS: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model. CONCLUSIONS: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias de Mama Triplo Negativas , Animais , Camundongos , Humanos , Dieta Redutora , Espécies Reativas de Oxigênio , ObesidadeRESUMO
Cancer health disparities remain stubbornly entrenched in the US health care system. The Affordable Care Act was legislation to target these disparities in health outcomes. Expanded access to health care, reduction in tobacco use, uptake of other preventive measures and cancer screening, and improved cancer therapies greatly reduced cancer mortality among women and men and underserved communities in this country. Yet, disparities in cancer outcomes remain. Underserved populations continue to experience an excessive cancer burden. This burden is largely explained by health care disparities, lifestyle factors, cultural barriers, and disparate exposures to carcinogens and pathogens, as exemplified by the COVID-19 epidemic. However, research also shows that comorbidities, social stress, ancestral and immunobiological factors, and the microbiome, may contribute to health disparities in cancer risk and survival. Recent studies revealed that comorbid conditions can induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. In this review, we will discuss unanswered questions and new opportunities in cancer health disparity research related to comorbid chronic diseases, stress signaling, the immune response, and the microbiome, and what contribution these factors may have as causes of cancer health disparities.
Assuntos
COVID-19 , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Neoplasias/epidemiologia , Humanos , SARS-CoV-2RESUMO
HMGN proteins localize to chromatin regulatory sites and modulate the cell-type specific transcription profile; however, the molecular mechanism whereby these ubiquitous nucleosome binding proteins affect gene expression is not fully understood. Here, we show that HMGNs regulate the expression of Rex1, one of the most highly transcribed genes in mouse embryonic stem cells (ESCs), by recruiting the transcription factors NANOG, OCT4 and SOX2 to an ESC-specific super enhancer located in the 5' region of Rex1. HMGNs facilitate the establishment of an epigenetic landscape characteristic of active chromatin and enhancer promoter interactions, as seen by chromatin conformation capture. Loss of HMGNs alters the local epigenetic profile, increases histone H1 occupancy, decreases transcription factors binding and reduces enhancer promoter interactions, thereby downregulating, but not abolishing Rex1 expression. ChIP-seq analyses show high colocalization of HMGNs and of REX1, a zinc finger protein, at promoters and enhancers. Loss of HMGNs preferentially reduces the specific binding of REX1 to these chromatin regulatory sites. Thus, HMGNs affects both the expression and the chromatin binding specificity of REX1. We suggest that HMGNs affect cell-type specific gene expression by modulating the binding specificity of transcription factors to chromatin.
Assuntos
Cromatina/genética , Epigênese Genética , Proteínas HMGN/genética , Fatores de Transcrição/genética , Animais , Sítios de Ligação/genética , Regulação da Expressão Gênica/genética , Proteínas HMGN/química , Histonas/genética , Camundongos , Células-Tronco Embrionárias Murinas , Proteína Homeobox Nanog/genética , Nucleossomos/genética , Fator 3 de Transcrição de Octâmero/genética , Regiões Promotoras Genéticas , Ligação Proteica/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição SOXB1/genéticaRESUMO
The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed genome-wide transcriptome analyses in an isogenic, triple negative breast cancer (TNBC/basal-like) progression cell lines using a 3D cell culture model. We identified significantly altered expression of 1853 lncRNAs, including ~500 natural antisense transcript (NATs) lncRNAs. A significant number of breast cancer-deregulated NATs displayed co-regulated expression with oncogenic and tumor suppressor protein-coding genes in cis. Further studies on one such NAT, PDCD4-AS1 lncRNA reveal that it positively regulates the expression and activity of the tumor suppressor PDCD4 in mammary epithelial cells. Both PDCD4-AS1 and PDCD4 show reduced expression in TNBC cell lines and in patients, and depletion of PDCD4-AS1 compromised the cellular levels and activity of PDCD4. Further, tumorigenic properties of PDCD4-AS1-depleted TNBC cells were rescued by exogenous expression of PDCD4, implying that PDCD4-AS1 acts upstream of PDCD4. Mechanistically, PDCD4-AS1 stabilizes PDCD4 RNA by forming RNA duplex and controls the interaction between PDCD4 RNA and RNA decay promoting factors such as HuR. Our studies demonstrate crucial roles played by NAT lncRNAs in regulating post-transcriptional gene expression of key oncogenic or tumor suppressor genes, thereby contributing to TNBC progression.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Estabilidade de RNA , RNA Antissenso/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Proteínas de Ligação a RNA/genética , Neoplasias de Mama Triplo Negativas/genética , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Ligação Proteica , RNA Antissenso/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Proinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER-) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and cyclooxygenase-2 (COX2) have been described as independent predictors of disease outcome. We further explore these findings by investigating the impact of their coexpression on breast cancer survival. Elevated coexpression of NOS2/COX2 proteins is a strong predictor of poor survival among ER- patients (hazard ratio: 21). Furthermore, we found that the key products of NOS2 and COX2, NO and prostaglandin E2 (PGE2), respectively, promote feed-forward NOS2/COX2 crosstalk in both MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines in which NO induced COX2 and PGE2 induced NOS2 proteins. COX2 induction by NO involved TRAF2 activation that occurred in a TNFα-dependent manner in MDA-MB-468 cells. In contrast, NO-mediated TRAF2 activation in the more aggressive MDA-MB-231 cells was TNFα independent but involved the endoplasmic reticulum stress response. Inhibition of NOS2 and COX2 using amino-guanidine and aspirin/indomethacin yielded an additive reduction in the growth of MDA-MB-231 tumor xenografts. These findings support a role of NOS2/COX2 crosstalk during disease progression of aggressive cancer phenotypes and offer insight into therapeutic applications for better survival of patients with ER- and TNBC disease.
Assuntos
Neoplasias da Mama/genética , Ciclo-Oxigenase 2/genética , Regulação Neoplásica da Expressão Gênica , Óxido Nítrico Sintase Tipo II/genética , Receptores de Estrogênio/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Aspirina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Guanidinas/farmacologia , Humanos , Indometacina/farmacologia , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Estrogênio/deficiência , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African American patients. Further analysis showed that these hypermethylated CpG islands in patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in bladder cancer progression. On follow-up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine, and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African American patients. Flux analysis experiments with 13C-labeled glucose in cultured African American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicate that race/ethnic differences in tumor biology may exist in bladder cancer.
Assuntos
Ilhas de CpG , Metilação de DNA , Inativação Metabólica/genética , Neoplasias da Bexiga Urinária/genética , Negro ou Afro-Americano/genética , Cromatografia Líquida , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Ácido Glucurônico/análise , Ácido Glucurônico/metabolismo , Humanos , Metabolômica , Regiões Promotoras Genéticas , S-Adenosil-Homocisteína/análise , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/análise , S-Adenosilmetionina/metabolismo , Espectrometria de Massas em Tandem , Neoplasias da Bexiga Urinária/metabolismo , População Branca/genéticaRESUMO
BACKGROUND: African Americans (AAs) experience a disproportionally high rate of bladder cancer (BLCA) deaths even though their incidence rates are lower than those of other patient groups. Using a metabolomics approach, this study investigated how AA BLCA may differ molecularly from European Americans (EAs) BLCA, and it examined serum samples from patients with BLCA with the aim of identifying druggable metabolic pathways in AA patients. METHODS: Targeted metabolomics was applied to measure more than 300 metabolites in serum samples from 2 independent cohorts of EA and AA patients with BLCA and healthy EA and AA controls via liquid chromatography-mass spectrometry, and this was followed by the identification of altered metabolic pathways with a focus on AA BLCA. A subset of the differential metabolites was validated via absolute quantification with the Biocrates AbsoluteIDQ p180 kit. The clinical significance of the findings was further examined in The Cancer Genomic Atlas BLCA data set. RESULTS: Fifty-three metabolites, mainly related to amino acid, lipid, and nucleotide metabolism, were identified that showed significant differences in abundance between AA and EA BLCA. For example, the levels of taurine, glutamine, glutamate, aspartate, and serine were elevated in serum samples from AA patients versus EA patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as malic enzyme 3, prolyl 3-hydroxylase 2, and lysine demethylase 2A that predicted patient survival exclusively in AA patients with BLCA. CONCLUSIONS: This metabolic profile of serum samples might be used to assess risk progression in AA BLCA. These first-in-field findings describe metabolic alterations in AA BLCA and emphasize a potential biological basis for BLCA health disparities.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Metabolômica/métodos , Neoplasias da Bexiga Urinária/sangue , População Branca/estatística & dados numéricos , Aminoácidos/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Humanos , Lipídeos/sangue , Masculino , Espectrometria de Massas , Redes e Vias Metabólicas , Análise de Sobrevida , Neoplasias da Bexiga Urinária/etnologia , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
PURPOSE: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Produtos Finais de Glicação Avançada/metabolismo , Estilo de Vida , Receptores de Estrogênio/metabolismo , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Sobreviventes de Câncer , Linhagem Celular Tumoral , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Feminino , Produtos Finais de Glicação Avançada/sangue , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico , Resultado do TratamentoRESUMO
Cancer mortality rates in the United States continue to decline. Reductions in tobacco use, uptake of preventive measures, adoption of early detection methods, and better treatments have resulted in improved cancer outcomes for men and women. Despite this progress, some population groups continue to experience an excessive cancer burden when compared with other population groups. One of the most prominent cancer health disparities exists in prostate cancer. Prostate cancer mortality rates are highest among men of African ancestry when compared with other men, both in the United States and globally. This disparity and other cancer health disparities are largely explained by differences in access to health care, diet, lifestyle, cultural barriers, and disparate exposures to carcinogens and pathogens. Dietary and lifestyle factors, pathogens, and ancestry-related factors can modify tumor biology and induce a more aggressive disease. There are numerous examples of how environmental exposures, like tobacco, chronic stress, or dietary factors, induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. Because of population differences in the exposure to these risk factors, they can be the cause of cancer disparities. In this review, we will summarize recent advances in our understanding of prostate and breast cancer disparities in the United States and discuss how the analysis of tumor biology can advance health disparity research.
Assuntos
Disparidades nos Níveis de Saúde , Neoplasias/etnologia , Negro ou Afro-Americano/estatística & dados numéricos , Pesquisa Biomédica/métodos , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Epigenômica , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estados Unidos/epidemiologiaRESUMO
The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.