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BACKGROUND: Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility. METHODS: We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway. RESULTS: Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway. CONCLUSIONS: These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Proteínas de la Membrana , Regiones Promotoras Genéticas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Masculino , Metilación de ADN/genética , Proteínas de la Membrana/genética , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Anciano , Regiones Promotoras Genéticas/genética , Proliferación Celular/genética , Movimiento Celular/genética , Vía de Señalización Wnt/genética , Línea Celular TumoralRESUMEN
Introduction: Bioelectrical impedance analysis (BIA) serves as a method to estimate body composition. Parameters such as phase angle (PA), standardized phase angle (SPA), body mass cell (BCM), BCM index (BCMI), and fat-free mass (FFM) might significantly impact the prognosis of head and neck cancer (HNC) patients. The present study aimed to investigate whether bioelectrical parameters can be used to predict survival in the HNC population and establish the optimal cutoff points for predictive accuracy. Methods: A multicenter observational study was performed across 12 tertiary hospitals in Andalusia (a region from the south of Spain). A total of 494 patients diagnosed with HNC between 2020 and 2022 at different stages were included in this study, with a minimum follow-up period of 12 months. The BIA assessment was carried out during the first 2 weeks of radical radiotherapy treatment with chemotherapy or other systemic treatments. A multivariate logistic regression analysis of overall survival, complications, hospital admission, and palliative care and its relationship with BIA nutritional assessment was performed. Results: Significant prognostic factors identified in the multivariable analysis encompassed phase angle (PA), standardized phase angle (SPA), body cell mass (BCM), and BCM index (BCMI). Lower PA and BCM values were significantly associated with adverse clinical outcomes. A BCM threshold above 17 kg/m2 was the most significant predictor for predicting survival within the overall HNC population. The PA values of <5.1° in male and <4.8° in female patients showed the best predictive potential for mortality. Increased PA (as a continuous variable) demonstrated a significantly reduced risk for mortality (OR, 0.64; 95% CI, 0.43-0.94; p < 0.05) and a decreased likelihood of hospital admission (OR, 0.75; 95% CI, 0.52-1.07; p < 0.05). Higher BCM correlated with a lower risk of mortality (OR, 0.88; 95% CI, 0.80-0.96; p < 0.01) and a diminished probability of hospital admission (OR, 0.91; 95% CI, 0.83-0.99; p < 0.05). Conclusion: BIA is a crucial tool in the nutritional assessment of HNC patients. BCM and PA are the main bioelectrical parameters used to predict clinical outcomes in this population. Future studies are needed to validate BIA variables in a large cohort to ensure whether early intensification of nutritional treatment would improve survival.
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Head and neck cancer (HNC) is a prevalent and aggressive form of cancer with high mortality rates and significant implications for nutritional status. Accurate assessment of malnutrition in patients with HNC is crucial for optimizing treatment outcomes and improving survival rates. This study aimed to evaluate the use of ultrasound techniques for predicting nutritional status, malnutrition, and cancer outcomes in patients with HNC. A total of 494 patients with HNC were included in this cross-sectional observational study. Various tools and body composition measurements, including muscle mass and adipose tissue ultrasound evaluations, were implemented. Using regression models, we mainly found that high levels of RF-CSA (rectus femoris cross-sectional area) were associated with a decreased risk of malnutrition (as defined with GLIM criteria (OR = 0.81, 95% CI: 0.68-0.98); as defined with PG-SGA (OR = 0.78, 95% CI: 0.62-0.98)) and sarcopenia (OR = 0.64, 95% CI: 0.49-0.82) after being adjusted for age, sex, and BMI. To predict the importance of muscle mass ultrasound variables on the risk of mortality, a nomogram, a random forest, and decision tree models were conducted. RF-CSA was the most important variable under the random forest model. The obtained C-index for the nomogram was 0.704, and the Brier score was 16.8. With an RF-CSA < 2.7 (AUC of 0.653 (0.59-0.77)) as a split, the decision tree model classified up to 68% of patients as possessing a high probability of survival. According to the cut-off value of 2.7 cm2, patients with a low RF-CSA value lower than 2.7 cm2 had worse survival rates (p < 0.001). The findings of this study highlight the importance of implementing ultrasound tools, for accurate diagnoses and monitoring of malnutrition in patients with HNC. Adipose tissue ultrasound measurements were only weakly associated with malnutrition and not with sarcopenia, indicating that muscle mass is a more important indicator of overall health and nutritional status. These results have the potential to improve survival rates and quality of life by enabling early intervention and personalized nutritional management.
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Neoplasias de Cabeza y Cuello , Desnutrición , Sarcopenia , Humanos , Estudios Prospectivos , Calidad de Vida , Sarcopenia/diagnóstico por imagen , Sarcopenia/etiología , Pronóstico , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Desnutrición/etiología , Estado Nutricional , Músculo Cuádriceps , Evaluación NutricionalRESUMEN
Vitamin D, microbiota, and the Mediterranean diet (MedDiet) have been the focus of recent research due to their potential role in maintaining overall health. We hypothesize that MedDiet may alter the gut microbiota profile through changes in vitamin D levels. We aimed to investigate changes in gut microbiota and serum vitamin D levels after a MedDiet within a lifestyle intervention. The study included 91 patients with obesity and metabolic syndrome, who were categorized based on their serum vitamin D levels as having either optimal or low 25-hydroxyvitamin D [25(OH)D levels]. The profile of the gut microbiota was analyzed by the 16S rRNA sequencing, inferring its functionality through PICRUsT. Participants underwent a hypocaloric MedDiet and change in their lifestyle for 1 year, and the profile and functionality of their gut microbiota were evaluated by analyzing inter-individual differences in time. At baseline, gut microbiota profiles qualitatively differed between participants with Optimal or Low 25(OH)D levels [Unweighted (p = 0.016)]. Moreover, participants with Optimal 25(OH)D levels showed a higher gut microbiota diversity than those with Low 25(OH)D levels (p < 0.05). The differential analysis of abundance between the Low and Optimal 25(OH)D groups revealed differences in the levels of Bacteroides, Prevotella, and two Clostridiales features. After 1-year dietary intervention, both groups increased their 25(OH)D levels. Furthermore, both groups did not show significant differences in gut microbiota diversity, although the Low 25(OH)D group showed greater improvement in gut microbiota diversity by comparing at baseline and after dietary intervention (p < 0.05). Changes in specific bacterial taxa were observed within each group but did not differ significantly between the groups. Metabolic pathway analysis indicated differences in microbial functions between the groups (p < 0.05). These findings suggest that 25(OH)D status is associated with gut microbiota composition, diversity, and functionality, and lifestyle intervention can modulate both gut microbiota and 25(OH)D levels, potentially influencing metabolic pathways.
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Dieta Mediterránea , Microbioma Gastrointestinal , Síndrome Metabólico , Humanos , Síndrome Metabólico/terapia , Estudios Prospectivos , Estudios Transversales , ARN Ribosómico 16S/genética , Obesidad/terapia , Vitamina D , Vitaminas , Estilo de VidaRESUMEN
DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)-a DNA repair enzyme-may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.
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Neoplasias Colorrectales , ADN Glicosilasas , Humanos , Neoplasias Colorrectales/genética , Daño del ADN , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Reparación del ADN/genética , Obesidad/complicaciones , Obesidad/genética , Factores de Riesgo , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
BACKGROUND: Patients with colorectal cancer (CRC) are largely malnourished, which decreases overall survival and treatment efficacy and increases mortality rates. We hypothesize that angle phase might be associated with the risk of sarcopenia as well as cancer complications in patients with CRC. The inclusion of various nutritional status indicators and clinical cancer outcomes can result in significant variability. Therefore, the objective of this study was to perform an exploratory analysis of nutritional evaluation tools used to assess body composition and muscle quality in patients with CRC, in order to predict cancer complications and survival rate. METHODS: A total of 127 patients with CRC were included in this study. Bioelectrical impedance analysis and body composition were performed, which we used to obtain phase angle (PhA) values. Muscle function was assessed by hand-grip strength (HGS) and muscle quality and adipose tissue depot were performed using ultrasound techniques. RESULTS: This study showed that there were significant differences in body composition between females and males, as well as in muscle quantity and quality. PhA was highly correlated with quadriceps rectus femoris of cross-sectional area (RF-CSA), circumference of quadriceps rectus femoris (RF-CIR), superficial subcutaneous abdominal fat (S-SAT), as well as HGS (p < 0.05). PhA was also correlated with water content in females, and with muscle mass and quality in males (p < 0.05). Specifically, we found that PhA was a good predictor for cancer complications in women and the risk of sarcopenia in men. In the linear model controlled for age and body mass index (BMI), high PhA value was associated with a decreased risk of complications in females (Odds Ratio (OR) = 0.15, 95% CI: 0.03-0.81, p < 0.05). High PhA value was associated with a decreased risk of sarcopenia in males (OR = 0.42, 95% CI: 0.19-0.95, p < 0.05). In addition, Receiving Operating Characteristics (ROC) curve analysis showed that PhA had a good diagnostic accuracy for detecting cancer complications in females (Area under curve (AUC) = 0.894, 95% CI: 0.88-0.89, p < 0.05) and the risk of sarcopenia in males (AUC = 0.959, 95% CI: 0.91-0.92, p < 0.05). CONCLUSIONS: PhA can accurately predict oncological complications in women and sarcopenia in men. These differences are relevant to understanding the nutritional status of patients with CRC and their personalized nutritional treatment.
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Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.
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Neoplasias Colorrectales , Vitaminas , Humanos , Vitaminas/uso terapéutico , Epigénesis Genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/metabolismo , Metilación de ADN , Vitamina A/metabolismo , Vitamina KRESUMEN
The associations between circulating vitamin D concentrations and total and site-specific colorectal cancer (CRC) incidence have been examined in several epidemiological studies with overall inconclusive findings. The aim of this systematic review and meta-analysis of both case-control and prospective cohort studies was to evaluate the association between CRC and circulating levels of vitamin D. The main exposure and outcome were circulating total 25(OH)D and CRC, respectively, in the overall population (i.e., all subjects). Two reviewers, working independently, screened all the literature available to identify studies that met the inclusion criteria (e.g., case-control or prospective cohort studies, published in English, and excluding non-original papers). Data were pooled by the generic inverse variance method using a random or fixed effect model, as approriate. Heterogeneity was identified using the Cochran's Q-test and quantified by the I2 statistic. Results were stratified by study design, sex, and metabolite of vitamin D. Sensitivity and subgroup analyses were also performed. A total of 28 original studies were included for the quantitative meta-analysis. Meta-analyses comparing the highest vs lowest categories, showed a 39% lower risk between levels of total 25(OH)D and CRC risk (OR (95% CI): 0.61 (0.52; 0.71); 11 studies) in case-control studies; whereas a 20% reduced CRC risk in prospective cohort studies (HR (95% CI): 0.80 (0.66; 0.97); 6 studies). Results in women mirrored main results, whereas results in men were non-significant in both analyses. Our findings support an inverse association between circulating vitamin D levels and CRC risk.
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Neoplasias Colorrectales , Vitamina D , Masculino , Humanos , Femenino , Estudios Prospectivos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Vitaminas , Estudios de Casos y ControlesRESUMEN
Mitochondrial epitranscriptomics refers to the modifications occurring in all the different RNA types of mitochondria. Although the number of mitochondrial RNA modifications is less than those in cytoplasm, substantial evidence indicates that they play a critical role in accurate protein synthesis. Recent evidence supported those modifications in mitochondrial RNAs also have crucial implications in mitochondrial-related diseases. In the light of current knowledge about the involvement, the association between mitochondrial RNA modifications and diseases arises from studies focusing on mutations in both mitochondrial and nuclear DNA genes encoding enzymes involved in such modifications. Here, we review the current evidence available for mitochondrial RNA modifications and their role in metabolic disorders, and we also explore the possibility of using them as promising targets for prevention and early detection. Finally, we discuss future directions of mitochondrial epitranscriptomics in these metabolic alterations, and how these RNA modifications may offer a new diagnostic and theragnostic avenue for preventive purposes. This article is categorized under: RNA Processing > RNA Editing and Modification.
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Enfermedades Mitocondriales , ARN , Humanos , ARN Mitocondrial/metabolismo , ARN/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mitocondrias/metabolismo , Procesamiento Postranscripcional del ARNRESUMEN
The Mediterranean diet (MD) is one of the healthiest ones and is associated with a lower incidence of cardiovascular and cerebrovascular diseases as well as cancer. Extra virgin olive oil (EVOO) is probably the most idiosyncratic component of this diet. EVOO has been attributed with many healthful effects, which may be due to its phenolic components, e.g. including hydroxytyrosol (HT). Recent studies suggest that EVOO and HT have molecular targets in human tissues and modulate epigenetic mechanisms. DNA methylation is one of the most studied epigenetic mechanisms and consists of the addition of a methyl group to the cytosines of the DNA chain. Given the purported health effects of EVOO (poly)phenols, we analyzed the changes induced by HT in DNA methylation, in a colorectal cancer cell line. Caco-2 cells were treated with HT for one week or with the demethylating agent 5'-azacytidine for 48 h. Global DNA methylation was assessed by ELISA. DNA bisulfitation was performed and Infinium Methylation EPIC BeadChips were used to analyze the specific methylation of CpG sites. We show an increase in global DNA methylation in Caco-2 cells after HT treatment, with a total of 32,141 differentially methylated (CpGs DMCpGs). Interestingly, our analyses revealed the endothelin receptor type A gene (EDNRA) as a possible molecular target of HT. In summary, we demonstrate that cellular supplementation with HT results in a specific methylome map and propose a potential gene target for HT.
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Neoplasias Colorrectales , Dieta Mediterránea , Humanos , Células CACO-2 , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Epigénesis Genética , Aceite de Oliva/farmacología , Fenoles/farmacologíaRESUMEN
Backgrounds: Vitamin D and testosterone deficiency have been widely related to obesity. However, only a few studies have investigated the effect of vitamin D on testosterone in the context of obesity, in which controversial results have been raised. Objectives: The purpose of this study was to determine the relationship between serum 25-hydroxyvitamin D (25(OH)D) and testosterone levels in young men with different grade of obesity. Design and methods: This cross-sectional study included 269 healthy young men with obesity (body mass index (BMI) ≥ 30 kg/m2). Participants were divided into two groups based on their serum 25(OH)D levels (134 subjects with vitamin D sufficiency and 135 participants with vitamin D deficiency, according to the 50th percentile of 25(OH)D). Serum 25(OH)D and sex hormones have been measured. The relationships between 25(OH)D, sex hormones, and obesity grades were investigated with linear and binary logistic regression analyses, as well as mediation analysis. Results: Compared to the 25(OH)D sufficiency group, total and free testosterone levels were found to be decreased, whereas serum androstenedione levels were increased in the 25(OH)D deficiency group (p<0.05). Using multivariable lineal regression analyses, 25(OH)D was correlated with the majority of sex hormones (p<0.05). When mediation with BMI was performed, the direct effect between 25(OH)D and sex hormones disappeared, and only the indirect effect via BMI remained (demonstrating the importance of BMI). Furthermore, after controlling for age and smoking status, we discovered that total testosterone and SHBG were both significantly associated with 25(OH)D (p<0.05) in subjects with obesity type III. Using a mediation analysis, we discovered that BMI had a partial effect on the association between 25(OH)D and total testosterone levels in morbidly obese participants, indicating that a direct association between 25(OH)D and total testosterone levels, and that BMI partially mediated this association. Conclusions: Serum 25(OH)D is associated with total testosterone levels in only those subjects with morbid obesity, suggesting a specific benefit in severe cases of obesity. Additional research is needed to elucidate possible common mechanisms.
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Obesidad Mórbida , Androstenodiona , Índice de Masa Corporal , Estudios Transversales , Hormonas Esteroides Gonadales , Humanos , Masculino , Testosterona , Vitamina D/análogos & derivadosRESUMEN
The production of plastic has dramatically increased in the last 50 y. Because of their stability and durability, plastics are ubiquitously incorporated in both marine and terrestrial ecosystems. Plastic is acted upon by biological, chemical, and physical agents, leading to fragmentation into small pieces [i.e., microplastics (MPs) or nanoplastics (NPs)], classified depending on their size. MPs range from 0.1 to 5000 µm and NPs are fragments between 0.001 to 0.1 µm. MPs and, especially NPs, are easily incorporated into living beings via ingestion. The penetration of MPs and NPs into the food system is an important issue, for both food security and health risk assessment. Ingestion of different MPs and NPs has been associated with different issues in the intestine, such as direct physical damage, increased intestinal permeability, diminished microbiota diversity, and increases in local inflammatory response. However, the potential harmful effects of low-dose dietary plastic are still unclear. Some evidence indicates that intestinal uptake of plastic particles is relatively low and is mostly dependent on the particle's size. However, other evidence highlights that NPs dysregulate key molecular signaling pathways, modify the gut microbiota composition, and may induce important epigenetic changes, including transgenerational effects that might be involved in the onset of many different metabolic disorders. Until now, experiments have been mostly performed on marine organisms, Caenorhabditis elegans, and mouse models, but some research indicates accidental plastic dietary consumption by humans, raising the issue of detrimental health effects of MPs and NPs. This review discusses the impact that MPs and NPs could have on the intestinal tract and the biodistribution and systemic, cellular, and molecular levels. Accumulated evidence of MPs' effects on the human gut suggests that large exposure to MPs and NPs may have phenotypical untoward effects in humans, calling for urgent research in this field.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Ecosistema , Epigénesis Genética , Humanos , Ratones , Microplásticos/toxicidad , Plásticos , Distribución Tisular , Contaminantes Químicos del Agua/análisisRESUMEN
BACKGROUND: Obesity was consistently associated with a poor prognosis in patients with COVID-19. Epigenetic mechanisms were proposed as the link between obesity and comorbidities risk. AIM: To evaluate the methylation levels of angiotensin-converting enzyme 2 (ACE2) gene, the main entry receptor of SARS-CoV-2, in different depots of adipose tissue (AT) and leukocytes (PBMCs) in obesity and after weight loss therapy based on a very-low-calorie ketogenic diet (VLCKD), a balanced hypocaloric diet (HCD) or bariatric surgery (BS). MATERIALS AND METHODS: DNA methylation levels of ACE2 were extracted from our data sets generated by the hybridization of subcutaneous (SAT) (n = 32) or visceral (VAT; n = 32) adipose tissue, and PBMCs (n = 34) samples in Infinium HumanMethylation450 BeadChips. Data were compared based on the degree of obesity and after 4-6 months of weight loss either by following a nutritional or surgical treatment and correlated with ACE2 transcript levels. RESULTS: As compared with normal weight, VAT from patients with obesity showed higher ACE2 methylation levels. These differences were mirrored in PBMCs but not in SAT. The observed obesity-associated methylation of ACE2 was reversed after VLCKD and HCD but not after BS. Among the studied CpG sites, cg16734967 and cg21598868, located at the promoter, were the most affected and correlated with BMI. The observed DNA methylation pattern was inversely correlated with ACE2 expression. CONCLUSION: Obesity-related VAT shows hypermethylation and downregulation of the ACE2 gene that is mirrored in PBMCs and is restored after nutritional weight reduction therapy. The results warrant the necessity to further evaluate its implication for COVID-19 pathogenesis.
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Enzima Convertidora de Angiotensina 2/genética , Grasa Intraabdominal/metabolismo , Leucocitos Mononucleares/metabolismo , Obesidad/genética , Receptores de Coronavirus/genética , Grasa Subcutánea/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enzima Convertidora de Angiotensina 2/metabolismo , Cirugía Bariátrica , COVID-19 , Metilación de ADN , Dieta Cetogénica , Dieta Reductora , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo , Obesidad/terapia , Obesidad Mórbida/genética , Obesidad Mórbida/metabolismo , Obesidad Mórbida/terapia , Receptores de Coronavirus/metabolismo , SARS-CoV-2 , Pérdida de PesoRESUMEN
Adipose tissue dysfunction, particularly the visceral (VAT) compartment, has been proposed to play a relevant role in colorectal cancer (CRC) development and progression. Epigenetic mechanisms could be involved in this association. The current study aimed to evaluate if specific epigenetic marks in VAT are associated with colorectal cancer (CRC) to identify epigenetic hallmarks of adipose tissue-related CRC. Epigenome-wide DNA methylation was evaluated in VAT from 25 healthy participants and 29 CRC patients, using the Infinium HumanMethylation450K BeadChip. The epigenome-wide methylation analysis identified 170,184 sites able to perfectly separate the CRC and healthy samples. The differentially methylated CpG sites (DMCpGs) showed a global trend for increased methylated levels in CRC with respect to healthy group. Most of the genes encoded by the DMCpGs belonged to metabolic pathways and cell cycle, insulin resistance, and adipocytokine signalling, as well as tumoural transformation processes. In gene-specific analyses, involved genes biologically relevant for the development of CRC include PTPRN2, MAD1L1, TNXB, DIP2C, INPP5A, HDCA4, PRDM16, RPTOR, ATP11A, TBCD, PABPC3, and IER2. The methylation level of some of them showed a discriminatory capacity for detecting CRC higher than 90%, showing IER2 to have the highest capacity. This study reveals that a specific methylation pattern of VAT is associated with CRC. Some of the epigenetic marks identified could provide useful tools for the prediction and personalized treatment of CRC connected to excess adiposity.
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Neoplasias Colorrectales , Grasa Intraabdominal , Tejido Adiposo/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Islas de CpG , Metilación de ADN , Epigénesis Genética , Epigenoma , Humanos , Grasa Intraabdominal/metabolismo , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
The field of epitranscriptomics is rapidly developing. Several modifications (e.g. methylations) have been identified for different RNA types. Current evidence shows that chemical RNA modifications can influence the whole molecule's secondary structure, translatability, functionality, stability, and degradation, and some are dynamically and reversibly modulated. miRNAs, in particular, are not only post-transcriptional modulators of gene expression but are themselves submitted to regulatory mechanisms. Understanding how these modifications are regulated and the resulting pathological consequences when dysregulation occurs is essential for the development of new therapeutic targets. In humans and other mammals, dietary components have been shown to affect miRNA expression and may also induce chemical modifications in miRNAs. The identification of chemical modifications in miRNAs (endogenous and exogenous) that can impact host gene expression opens up an alternative way to select new specific therapeutic targets.Hence, the aim of this review is to briefly address how RNA epitranscriptomic modifications can affect miRNA biogenesis and to summarize the existing evidence showing the connection between the (de)regulation of these processes and disease settings. In addition, we hypothesize on the potential effect certain chemical modifications could have on the potential cross-kingdom journey of dietary plant miRNAs.
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Susceptibilidad a Enfermedades , Epigénesis Genética , MicroARNs/genética , Procesamiento Postranscripcional del ARN , Regiones no Traducidas 3' , Adenosina/análogos & derivados , Animales , Emparejamiento Base , Sitios de Unión , Regulación de la Expresión Génica de las Plantas , Humanos , Metilación , Interferencia de ARN , TranscriptomaRESUMEN
A dysfunctional visceral adipose tissue (VAT) is characterized by increased production of proinflammatory cytokines, which may increase the risk of colorectal cancer (CRC). However, the epigenetic contribution to the inflammatory status is poorly understood. In our study, we hypothesized that a dysfunctional VAT may be a risk factor for CRC, through epigenetic modifications. Therefore, we aimed to study the transcriptional/methylation profile of proinflammatory cytokines and genes related to vitamin D metabolism in VAT from CRC patients, and evaluate their association with serum 25-hydroxyvitamin D (25(OH)D). We included 129 participants (68 healthy participants and 61 CRC patients). We found that the majority of the studied genes are upregulated and hypomethylated in CRC patients, when compared to the healthy subjects (p < 0.05). In addition, serum 25(OH)D was associated with both mRNA gene expression and methylation of key genes, such as interleukin (IL)6, IL10, vitamin D receptor (VDR) or cytochrome P450 subfamily 27 type B1 (CYP27B1) (p < 0.05). Interestingly, while high IL6 expression was related to poor survival in CRC (p < 0.05), IL6 methylation was associated with an increased risk of CRC, in which 25(OH)D partially mediated this association (p < 0.05). Our study suggests a potential association between epigenetic regulation of inflammatory mediators in VAT - such as IL6 - in the CRC context, in which 25(OH)D may mediate this risk. Therefore, vitamin D could affect the epigenetic status of IL6, which can be considered for additional preventive strategies.
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Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Interleucina-6/metabolismo , Grasa Intraabdominal/metabolismo , Vitamina D/análogos & derivados , Estudios de Casos y Controles , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Epigénesis Genética , Femenino , Humanos , Masculino , Metilación , Persona de Mediana Edad , España , Análisis de Supervivencia , Vitamina D/metabolismoRESUMEN
INTRODUCTION: Vitamin D has been widely associated with colorectal cancer (CRC) through different insights. This study aims to explore the association between serum 25-hydroxyvitamin D (25(OH)D) and the global DNA methylation in tumor from CRC patients. METHODS AND RESULTS: A genome-wide DNA methylation analysis is conducted in 20 CRC patients under categorical (10 patients have 25(OH)D <30 ng mL-1 ; 10 patients with 25(OH)D ≥30 ng mL-1 ) and continuous models of 25(OH)D. A total of 95 differentially methylated CpGs (DMCpGs) are detected under the categorical model (false discovery rate (FDR) < 0.05), while 16 DMCpGs are found under the continuous model. Regional analysis showed eight vitamin D-associated differentially methylated regions (DMR). Between them, a DMR is the most significant at cAMP-Dependent Protein Kinase Inhibitor Alpha (PKIA) locus. Furthermore, seven genes, including PKIA gene, have more or equal than two significant DMCpGs. The protein networking analysis found pathways implicated in cell adhesion and extracellular matrix, as well as signaling transduction. CONCLUSIONS: This study identifies novel epigenetic loci associated with serum 25(OH)D status. Interestingly, also, a positive association between vitamin D and DNA methylation in the CRC context is found, suggesting a role in CRC. Further studies are warranted to clarify and replicate these results.
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Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Metilación de ADN , Vitamina D/análogos & derivados , Anciano , Islas de CpG , Variaciones en el Número de Copia de ADN , Epigénesis Genética , Femenino , Ontología de Genes , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Persona de Mediana Edad , Vitamina D/sangre , Vitamina D/genéticaRESUMEN
Obesity, a sedentary lifestyle, high red meat consumption and alcohol, and tobacco are considered the driving factors behind colorectal cancer (CRC) worldwide. Both diet and lifestyle are recognized to play an important role in the prevention of CRC. Forty years later, the vitamin D-cancer hypothesis is considered consistent. However, the relationship between low vitamin D intake and CRC is still controversial. The aim of this meta-analysis is to determine the associations between Vitamin D intake and CRC. MEDLINE-PubMed and Cochrane databases were searched up to May 2020 for studies evaluating the association between vitamin D intake (from foods and supplements) and CRC. Two reviewers, working independently, screened all titles and abstracts to identify the studies that met the inclusion criteria (case-control or prospective cohort (PC) studies published in English). Data were pooled by the generic inverse variance method using a random or fixed effect model. Heterogeneity was identified using the Cochran Q-test and quantified by the I2 statistic. A total of 31 original studies were included for the quantitative meta-analysis, comprising a total 47.540 cases and 70.567 controls in case-control studies, and a total of 14.676 CRC-incident cases (out of 808.130 subjects in PC studies) from 17 countries. A significant 25% lower risk was reported comparing the highest vs. the lowest dietary vitamin D consumption and CRC risk (odds ratio (95% confidence interval): 0.75 (0.67; 0.85)) in case-control studies, whereas a non-significant association was reported in case of prospective studies (hazard ratio (95% confidence interval): 0.94 (0.79; 1.11). The present meta-analysis demonstrates that high dietary vitamin D is associated to CRC prevention. However, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.
RESUMEN
PURPOSE: We evaluated whether the intake of dietary vitamin D is associated with the incidence of both colorectal cancer (CRC) and colon cancer in the framework of the PREDIMED cohort of older adults at high cardiovascular risk. METHODS: We analyzed data from 7216 men and women (55-80 years) without CRC at baseline from the PREvención con DIeta MEDiterránea study. Baseline consumption of vitamin D was assessed using a validated 137-item food frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC and colon cancer incidence were estimated for quartiles and per 1-SD of baseline vitamin D intake. RESULTS: During a median follow-up of 6 years, we documented 97 incident CRC cases after the exclusion of subjects with no baseline dietary data and/or outliers of energy intake. A non-significant HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme quartiles (4th vs 1st) of vitamin D intake were observed [0.55 (0.30-1.00), P for trend = 0.072], whereas it was significant for colon cancer incidence alone [0.44 (0.22-0.90), P for trend = 0.032]. However, this association became significant in CRC and colon cancer incidence, after excluding 391 subjects consuming baseline vitamin D and/or calcium medication or prescribed supplements [0.52 (0.28-0.96) and 0.41 (0.12-0.85), respectively]. CONCLUSION: A higher dietary intake of vitamin D was significantly associated with a reduced CRC risk in individuals at high cardiovascular risk.