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Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.
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Peganum harmala has been extensively employed in Algerian traditional medicine practices. This study aimed to explore the impact of n-butanol (n-BuOH) extract sourced from Peganum harmala seeds on cell proliferation, cell migration, and angiogenesis inhibition. Cytotoxic potential of n-BuOH extract was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide) assay against human breast adenocarcinoma MCF-7 cells, cell migration was determined using scratch assay, and anti-angiogenic effect was evaluated through macroscopic and histological examinations conducted on chick embryo chorioallantoic membrane. Additionally, this research estimated the phytochemical profile of n-BuOH extract. Fifteen phenolic compounds were identified using Ultra-performance liquid chromatography UPLC-ESI-MS-MS analysis. In addition, the n-BuOH extract of P. harmala exhibited potent antioxidant and free radical scavenging properties. The n-BuOH extract showed potent cytotoxicity against MCF-7 cell with an IC50 value of 8.68 ± 1.58 µg/mL. Furthermore, n-BuOH extract significantly reduced migration. A strong anti-angiogenic activity was observed in the groups treated with n-BuOH extract in comparison to the negative control. Histological analysis confirmed the anti-angiogenic effect of the n-BuOH extract. This activity is probably a result of the synergistic effects produced by different polyphenolic classes.
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Inhibidores de la Angiogénesis , Movimiento Celular , Peganum , Fenoles , Extractos Vegetales , Humanos , Movimiento Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Peganum/química , Embrión de Pollo , Fenoles/farmacología , Fenoles/análisis , Inhibidores de la Angiogénesis/farmacología , Células MCF-7 , Animales , Proliferación Celular/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/química , Antioxidantes/farmacología , Antioxidantes/química , Antineoplásicos Fitogénicos/farmacología , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/irrigación sanguíneaRESUMEN
BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurring fever, erythema, joint pain, and abdominal discomfort during acute episodes. While FMF patients typically share MEFV gene mutations, they display varying clinical manifestations, suggesting the involvement of modifying genes, epigenetic mechanisms, or environmental factors. G protein regulator signal 10 (RGS10), a member of the RGS protein family, exhibits anti-inflammatory effects in autoinflammatory diseases. There are no studies on the role of plays in FMF pathogenesis or histone modification in FMF. AIMS: This study aimed to shed light on the epigenetic regulation of FMF from several perspectives. The relationship between RGS10 DNA hypermethylation in FMF clinical parameters and the regulation of 22 histone modifications were examined in FMF attack patients and the control group. METHODS: Sixty FMF (remission/attack) and thirty healthy individuals were included in the study. First, RNA was isolated from the blood of patients/controls, and the expression of RGS10 was examined. Then, DNA was isolated from the patients, and gene-specific hypermethylation was investigated using the bisulfite conversion method. Finally, histone extraction was performed for FMF patients and controls and 22 histone H3 modifications were determined. In addition, using ADEX bioinformatics tools, RGS10 expression and methylation profiles were detected in different autoinflammatory diseases. RESULTS: This study indicate that RGS10 expression decreased in attack-free/attack patients than control, attributed to DNA methylation. In addition, there were a positive correlation between FMF patients and attack, WBC, neutrophil, MCHC and MPV. Moreover, higher H3K4 me3, H3K9 me2, and H3K14ac levels were observed in patients with FMF attacks. This research also showed a consistent decrease in RGS10 expression in patients with SjS, SSc, and T1D compared with controls. I also obtained five prognosis-related CpGs (cg17527393, cg19653161, cg20445950, cg18938673 and cg13975098) of RGS10 in patients with SjS, RA, SSc, SLE and T1D. CONCLUSION: The present study provides insights into the complex relationship between RGS10, epigenetic modifications, and immune responses in FMF. While RGS10 may initially enhance immune responses, genetic mutations and epigenetic changes associated with FMF acute episode may override this regulatory effect, resulting in increased inflammation and clinical symptoms. Moreover, our study revealed elevated levels of specific histone modifications in the context of FMF, suggesting significant epigenetic changes that could contribute to the disease pathogenesis. Understanding these associations opens new avenues for research and potential therapeutic interventions, potentially involving epigenetic therapies targeting histone modifications.
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Diabetes Mellitus Tipo 1 , Fiebre Mediterránea Familiar , Proteínas RGS , Humanos , Fiebre Mediterránea Familiar/genética , Código de Histonas , Histonas/genética , Epigénesis Genética , Diabetes Mellitus Tipo 1/genética , Inflamación/genética , ADN , Pirina/genética , Proteínas RGS/genéticaRESUMEN
Pancreatic cancer (PC) is one of the world's most aggressive and deadly cancers, owing to non-specific early clinical symptoms, late-stage diagnosis, and poor survival. Therefore, it is critical to identify specific biomarkers for its early diagnosis. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein that has been reported to be upregulated in several cancer types, making it an emerging biomarker and potential cancer therapeutic target. However, the mechanism underlying the regulation of ANXA2 overexpression is still unclear. It is well established that genetic and epigenetic alterations may lead to widespread dysregulation of gene expression. Hence, in this study, we focused on exploring the regulatory mechanism of ANXA2 by investigating the transcriptional profile, methylation pattern, somatic mutation, and prognostic value of ANXA2 in PC using several bioinformatics databases. Our results revealed that the expression levels of ANXA2 were remarkably increased in PC tissues comparing to normal tissues. Furthermore, the high expression of ANXA2 was significantly related to the poor prognosis of PC patients. More importantly, we demonstrated for the first time that the ANXA2 promoter is hypomethylated in PC tissues compared to normal tissues which may result in ANXA2 overexpression in PC. However, more experimental research is required to corroborate our findings.
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GALNT7 is a glycosyltransferase enzyme transferring N-acetylgalactosamine to initiate O-linked glycosylation in the Golgi apparatus. Breast cancer is the most common cancer in women globally. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2; ERBB2) are important biomarkers in the prognosis and molecular subtyping of breast cancer. Here, we showed that ER-positive, PR-positive or HER2-positive breast tumors have higher expression of GALNT7 compared to ER-negative, PR-negative or HER2-negative breast tumors, respectively. We found that CpG-aggregated methylation of GALNT7 gene is decreased, and in parallel, its transcript levels are increased in breast cancer compared to healthy breast tissue. We observed that the difference in the expression of GALNT7 between negative and positive status of the receptors is the highest for HER2, followed by ER and PR, pointing that HER2 might be relatively more influential than ER and PR on the expression of GALNT7 in breast cancer. We reported that basal-like breast tumors have decreased expression of GALNT7 compared to non-basal-like tumors, and that high GALNT7 expression is associated with favorable relapse-free and distant metastasis-free survival in HER2 status-dependent manner in breast cancer patients. Moreover, we showed that GALNT7 expression in breast cancer is cell type- (epithelial vs stromal cells), tumor grade- and ethnicity-dependent. Combined, we propose that GALNT7 might contribute to different clinical outcomes depending on the receptor status in breast cancer, and that a better understanding of GALNT7 and its function in the context of breast cancer is needed.
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Neoplasias de la Mama , Receptor ErbB-2 , Femenino , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Estrógenos , Glicosiltransferasas , Progesterona , Pronóstico , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
Colorectal cancer is one of the most common cancers worldwide, affecting the colon and rectum. A major problem in the treatment of colorectal cancer is acquired chemoresistance, including resistance against death receptor-induced apoptosis. Therefore, investigating new biomarkers for the treatment of the disease and sensitization strategies against TRAIL might be of high clinical importance. TNFRSF10A/B are known as death receptors for TRAIL-induced apoptotic cell death. In this study, we used multiple bioinformatic tools and experimental analyses to investigate the role of TRAIL receptors TNFRSF10A and TNFRSF10B in colorectal cancer. We also identified the potential effect of bortezomib and epirubicin in the induction of TRAIL-mediated apoptotic cell death. Here, we showed that TNFRSF10 A/B expressions are upregulated in various tumor types, including COAD, and its high expression is decreased with the different clinicopathological parameters in COAD. We also found an association between TNFRSF10 A/B expression and tumor molecular subtypes. We further detected the association between the expression of TNFRSF10 A/B and immune cell tumor infiltration, including B cells, CD8+ T cells, neutrophils and dendritic cells. In addition, we showed that combining bortezomib and epirubicin treatment leads to the upregulation of TNFRSF10 A/B in colorectal cancer cells in vitro. The increase in the expression of death receptors was correlated with higher active caspase-3 levels following the incubation of cells with recombinant TRAIL protein, which is a ligand for TNFRSF10 A/B receptors. Our results suggest that TNFRSF10 A/B may be a marker to differentiate tumor molecular subtypes in colorectal cancer. The expression of TNFRSF10 A/B may be associated with the recruitment of immune cells into tumors and the development of tumor suppression. The combination of bortezomib and epirubicin treatment might sensitize colorectal cancer cells to TRAIL-induced apoptosis via the upregulation of death receptor.
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Linfocitos T CD8-positivos , Neoplasias Colorrectales , Humanos , Apoptosis , Bortezomib/farmacología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Epirrubicina/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
Immunological capability shows a sexual dimorphism in diverse animal species. Females are generally more immunocompetent than males, leading to the higher susceptibility of males to infection compared to females and thus greater infection-related pathology in males. These sex-differences in immunity remain understudied in birds. Here, we compared the percentage of parasitemia of three different parasite lineages belonging to the morphological species Haemoproteus majoris (namely, PARUS1, PHSIB1 and WW2) in terms of the sex of birds living in a natural community. We found that parasitemia (percentage of erythrocytes infected with parasites) of WW2 lineage, but not of the other two lineages of H. majoris, is higher in male birds compared to female birds. Similarly, we showed that the total parasitemia of these three H. majoris lineages is higher in male birds compared to female birds. Our study points out that male birds at the community level may be more susceptible to infection by certain parasites than female birds. We propose that sexual dimorphism in parasitemia of certain parasites in host birds might be more common than previously thought, similar to what is observed in other species, influencing host population dynamics in a sex-specific manner. Therefore, it can be speculated that infection by certain parasites might differentially affect male and female birds, possibly resulting in a bias in survival rates between sexes due to infections, in certain contexts.
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Enfermedades de las Aves , Haemosporida , Parásitos , Infecciones Protozoarias en Animales , Animales , Femenino , Masculino , Parasitemia/parasitología , Enfermedades de las Aves/parasitología , Aves/parasitología , Infecciones Protozoarias en Animales/parasitología , FilogeniaRESUMEN
Pyroptosis is a form of lytic cell death with pro-inflammatory characteristics, induced upon the activation of certain inflammatory caspases by inflammasome complexes such as NLRP3 inflammasome. Gasdermin proteins as the mediators of pyroptosis form cell membrane pores upon activation, which release certain cellular contents into the extracellular space including inflammatory cytokines such as IL-1ß and IL-18, and also damage the integrity of the cell membrane. Gasdermins have been implicated in autoimmune and inflammatory diseases, infectious diseases, deafness and cancer. Mostly in the last 2 years, diverse pollutant types including particulate matter, cadmium and polystyrene microplastics were reported to induce pyroptotic cell death in diverse tissues from mammals to birds. In the present study, we review our current understanding of pollutant-induced pyroptosis as well as current knowledge of upstream events leading to pyroptotic cell death upon exposure to pollutants.
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Inflamasomas , Piroptosis , Animales , Humanos , Inflamasomas/metabolismo , Plásticos , Caspasas/metabolismo , Citocinas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Mamíferos/metabolismoRESUMEN
Certain dietary supplements such as trans-10, cis-12 conjugated linoleic acid (t10-c12 CLA), and diets including caloric-restricted diets can promote weight loss in certain animal models and humans. A very recent study showed that exercise induces the biosynthesis of N-lactoyl-phenylalanine (Lac-Phe), a circulating signaling metabolite that suppresses feeding and obesity selectively in mice fed with a high-fat diet, and that cytosolic nonspecific dipeptidase 2 (CNDP2) catalyzes the synthesis of Lac-Phe from lactate (Lac) and phenylalanine (Phe). In this in silico study, we found that two anti-obesity strategies, namely treatment with t10-c12 CLA and caloric restriction, increase CNDP2 expression in adipose tissue in mice and rats, respectively. We showed that the effect of t10-c12 CLA on CNDP2 expression might be isomer-specific. We hypothesized that these t10-c12 CLA treatment- or caloric-restricted diet-mediated increases in CNDP2 expression might contribute to their anti-obesity effects, possibly due to increased Lac-Phe levels and ultimately due to Lac-Phe-mediated decreases in daily food consumption, reduced body weight and fat mass. A better understanding of the regulation of CNDP2 expression in diverse tissues in mammals might be of high importance in the treatment of obesity, considering its role in the synthesis of Lac-Phe, a metabolite that decreases body weight and fat mass selectively in mice fed with a high-fat diet. Further research is needed to find out how these two strategies lead to the upregulation of CNDP2 expression and whether this increased expression of CNDP2 might translate to reduced body weight and fat mass through higher Lac-Phe levels.
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Dipeptidasas , Ácidos Linoleicos Conjugados , Ratones , Humanos , Ratas , Animales , Ácidos Linoleicos Conjugados/farmacología , Restricción Calórica , Roedores/metabolismo , Regulación hacia Arriba , Hígado/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Peso Corporal , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa/efectos adversos , Dipeptidasas/metabolismo , Dipeptidasas/farmacologíaRESUMEN
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by variations in the MEFV gene, which encodes the pyrin protein, a member of the inflammasomes. Despite the complex pathogenesis of FMF, epigenetic changes also play roles in the disease progression. In our previous study, we observed a relationship between NLRP13, which is one of the members of the inflammasome complex and has a pyrin domain in its structure, and the MEFV gene using the STRING database. In this study, we examined NLRP13 expression and methylation status in 40 patients with FMF attack and 20 healthy individuals. We then investigated the global DNA methylation status of patients with FMF in the attack period and control groups. We further examined the relationship between the clinical manifestation and global methylation as well as NLRP13 gene expression of patients with FMF and healthy individuals. As a result, we showed that hypomethylation in patients with FMF leads to different clinical outcomes in terms of disease severity. In addition, the data indicated that NLRP13 inflammasome is epigenetically controlled in patients with FMF and the presence of amyloidosis may affect the hypermethylation of this gene. Moreover, NLRP13 was silenced because of the hypermethylation of the promoter. The increase of methylation level at the promoter region participated in the inactivation of NLRP13. In the current study, we not only found a new gene that plays a role in the pathogenesis of FMF disease, but also new evidence for the epigenetic regulation of the disease.
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Fiebre Mediterránea Familiar , Humanos , Fiebre Mediterránea Familiar/genética , Fiebre Mediterránea Familiar/patología , Inflamasomas/genética , Inflamasomas/metabolismo , Epigénesis Genética , Pirina/genética , Metilación de ADN , Gravedad del Paciente , MutaciónRESUMEN
Gasdermin proteins (GSDMs) form pores in cell membranes upon various stimuli, leading to the release of certain proinflammatory molecules such as IL-1ß and IL-18, and this ultimately results in pyroptotic cell death. NINJ1 (Ninjurin 1) has recently been identified as a cell membrane protein responsible for the final complete plasma membrane rupture following lytic cell death mechanisms including pyroptosis, causing the release of relatively larger molecules such as HMGB1 and LDH. In this study, we reported the presence of higher GSDMD and lower GSDME protein levels in ovarian tumors compared to surrounding non-malignant stroma in the tumor microenvironment. GSDME protein levels are also lower in the tumors of the omentum compared to adjacent stromal cells. We found that NINJ1 expression decreases from early to late stage in serous ovarian cancer, and the percentage of NINJ1 copy number loss events is the highest in ovarian cancer among other cancers. Moreover, we showed that low expression of NINJ1 is associated with shorter overall survival of patients with ovarian cancer. In support of the findings showing that low NINJ1 expression contributes to worse prognosis in this most lethal gynecological malignancy, NINJ1 expression was found to be lower in cisplatin-resistant ovarian cancer cells compared to cisplatin-sensitive counterparts in vitro. We suggest that the members of gasdermin family might have distinct functions in serous ovarian cancer, and low levels of NINJ1 might contribute, at least in part, to the progression and poorer prognosis of ovarian cancer. A complete picture of how pyroptosis and subsequent plasma membrane rupture are involved in ovarian cancer will be of high importance in order to identify actionable therapeutic vulnerabilities within this newly identified group of proteins.
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Cisplatino , Neoplasias Ováricas , Humanos , Femenino , Gasderminas , Membrana Celular , Pronóstico , Neoplasias Ováricas/metabolismo , Microambiente Tumoral , Factores de Crecimiento Nervioso , Moléculas de Adhesión Celular Neuronal/metabolismoRESUMEN
Natural killer group 2D ligands (NKG2DLs) are expressed on tumor cells as a ligand for Natural killer group 2D (NKG2D) receptors. NKG2DLs interact with NKG2D to induce immune cell-mediated cytotoxicity for eliminating tumors. Studies demonstrated that tumor cells can reduce NKG2DLs' expression to escape from anti-tumor immunity, leading to an aggressive cancer phenotype and poor prognosis in some cancers. However, these studies are limited and there is no comprehensive work on the regulation of NKG2DLs in lung adenocarcinoma (LUAD) which is one of the deadliest cancers worldwide. Here, we conducted an in silico analysis to evaluate the changes in NKG2DLs in LUAD by analyzing The Cancer Genome Atlas and the Gene Expression Omnibus datasets including tumor vs. normal comparisons, TNM stages, survival and infiltrating immune estimation profile. Results indicated that some members of NKG2DL were downregulated in LUAD as compared to normal samples. We determined that MICA (MHC class I polypeptide-related sequence A) was the most and significantly downregulated ligand among others and the results were nearly consistent with the different datasets which we used. Furthermore, survival analysis revealed that down-regulated MICA transcript expression might be one of the prognostic indicators of LUAD. Interestingly, according to the immune cell infiltrating analysis, there wasn't a direct correlation between the MICA transcript expression and immune cell infiltration, while for MICB there was. In addition, in genetic alteration, DNA methylation and miRNA analyses, we did not observe critical outcomes that would clarify the down-regulated MICA expression in detail. Regardless, this study is highly comprehensive and contributes valuable suggestions to further functional studies about the regulation of NKG2DLs and promising immunotherapeutic approaches in LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Células Asesinas Naturales , Ligandos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismoRESUMEN
Predation is a psychological stressor in prey animals. Besides direct killing and consumption by predators, the perception of predation risk indirectly influence prey population behavior, dynamics and physiology. Few studies identified the transcriptomic response associated with predator presence/abundance in natural populations and uncontrolled settings. However, to our knowledge, intersexual differences in the number of genes whose expression change in response to high predation risk have not been previously reported in wild mammals. Here, by using publicly available gene expression data in wild yellow-bellied marmots (Marmota flaviventer), we found that the number of differentially expressed genes in response to predator stress is higher in female marmots (n = 516) than males (n = 387). Only a small percentage of these differentially expressed genes (n = 36) are shared between the sexes, and that the most of the differentially expressed genes are expressed in a sex-specific manner in response to predation stress. Overall, our results provide new insight into sex-specific variation in gene expression changes in wild mammals under high predation risk.
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Mamíferos , Conducta Predatoria , Animales , Femenino , Masculino , Conducta Predatoria/fisiologíaRESUMEN
Colorectal cancer is known as the third most common cancer in both women and men. Genetic and epigenetic changes are major players contributing to colorectal carcinogenesis. Regulator of G-protein signaling 10 (RGS10) is a member of the RGS proteins, which negatively regulate several signaling pathways including cell survival and proliferation. We and others have previously shown that RGS10 expression is modulated by epigenetic modifications in ovarian cancer and suppression of RGS10 partially contributes to chemoresistance. Here, we further analyzed the roles and regulation of RGS10 in colon adenocarcinoma (COAD), using broad bioinformatics tools. We analyzed the expression profiles, promoter methylation state, prognostic value and effect of a hypomethylating agent on RGS10 expression. Results showed that RGS10 expression is higher in normal colon tissues than in tumor tissues. In addition, there is a negative correlation between DNA methylation and RGS10 transcript expression. We also observed that gene expression and promoter methylation of RGS10 in colorectal carcinoma patients were differently expressed depending on the tumor stage and microsatellite stability. DNA methylation was significantly increased in 18 probes of RGS10, which belongs to the high-risk group in COAD. In addition, pharmacological inhibition of DNA methyltransferase with decitabine reduced the six CpGsite-specific RGS10 hypermethylation in COAD. We also experimentally confirmed that RGS10 promoter activity was inhibited by treatment with decitabine in the HT-29 colorectal cell line. We further showed that decitabine treatment increases the RGS10 transcript expression in three different colorectal carcinoma cell lines. These results suggest that RGS10 expression is suppressed in the development of colorectal cancer and inhibition of DNA methylation may contribute to increasing overall survival rates of COAD patients.
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Adenocarcinoma , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Ováricas , Proteínas RGS , Adenocarcinoma/genética , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias Colorrectales/patología , Metilación de ADN/genética , Decitabina/metabolismo , Decitabina/farmacología , Decitabina/uso terapéutico , Femenino , Proteínas de Unión al GTP/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Neoplasias Ováricas/patología , Proteínas RGS/genética , Proteínas RGS/metabolismo , Tasa de SupervivenciaAsunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores de Tumor , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de ProgesteronaRESUMEN
CEP89 (centrosomal protein 89) is required for ciliogenesis and mitochondrial metabolism, but its role in cancer has yet to be clarified. We report that CEP89 is overexpressed in ovarian cancer (OC) compared to normal ovaries. Likewise, its expression is higher in malignant ovarian tumors than in borderline ovarian tumors with low malignant potential. More than a quarter of patients with OC have copy number gains in the CEP89 gene, and patients with high expression have more than a year shorter overall survival compared to those with low expression. Moreover, we found that CEP89 can be considered as a prognostic marker for poor overall survival in patients with OC, after adjusting for tumor stage and residual tumor. Nine out of the top 10 protein interactors of CEP89 have the highest percentage of total copy number variation (CNV) events in OC among all other cancer types. Furthermore, CEP89 messenger RNA (mRNA) levels are higher in OC patients with disease recurrence compared to those with no recurrence. We also analyzed CEP89 levels in OC cell lines in terms of CNV, mRNA, and protein levels; and observed that the FUOV-1 cell line has the highest levels among cell lines that originated from primary sites. Our study suggests that CEP89 may be a valuable prognostic predictor for the overall survival of patients with OC, and it could also be a novel therapeutic target in this malignancy.
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Variaciones en el Número de Copia de ADN , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/metabolismo , ARN Mensajero/genéticaRESUMEN
Cisplatin is a platinum-based chemotherapeutic drug used in the standard treatment of various solid cancers including testicular, bladder, head and neck, cervical and ovarian cancer. Although successful clinical responses are observed in patients following initial cisplatin treatment, resistance to cisplatin ultimately develops in most patients, leading to therapeutic failure. Multiple molecular mechanisms contributing to cisplatin resistance in cancer cells have been identified to date. In this review, we discuss the effect of estrogen, estrogen receptors (ERs) and estrogen-related receptors (ERRs) on cisplatin resistance in various cancer types. We highlight that estrogen treatment or increased expression of ERs or ERRs are generally associated with higher cisplatin resistance in cancer in vitro, mostly due to decreased caspase activity, increased anti-apoptotic protein levels such as BCL-2, higher drug efflux and higher levels of antioxidant enzymes. Targeted inhibition of ERs or estrogen production in combination with cisplatin treatment thus can be a useful strategy to overcome chemoresistance in certain cancer types. Estrogen levels and ER status can also be considered to identify cancer patients with a high potential of therapy response against cisplatin. A better mechanistic understanding of the involvement of estrogen, ERs and ERRs in the development of cisplatin resistance is needed to improve the management of cancer treatment.
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Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Neoplasias/tratamiento farmacológico , Receptores de Estrógenos/fisiología , Femenino , HumanosRESUMEN
Research on aging and lifespan-extending compounds has been carried out using diverse model organisms, including yeast, worms, flies and mice. Many studies reported the identification of novel lifespan-extending compounds in different species, some of which may have the potential to translate to the clinic. However, studies collectively and comparatively analyzing all the data available in these studies are highly limited. Here, by using data from the DrugAge database, we first identified top compounds in terms of their effects on percent change in average lifespan of diverse organisms, collectively (n = 1728). We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. We showed that minocycline led to the highest percent increase in average lifespan among other compounds, in both Drosophila melanogaster (28.09%) and Caenorhabditis elegans (26.67%), followed by curcumin (11.29%) and gluconic acid (5.51%) for D. melanogaster and by metformin (26.56%), resveratrol (15.82%) and quercetin (9.58%) for C. elegans. Moreover, we found that top 5 species whose lifespan can be extended the most by compounds with lifespan-extending properties are Philodina acuticornis, Acheta domesticus, Aeolosoma viride, Mytilina brevispina and Saccharomyces cerevisiae (211.80%, 76%, 70.26%, 55.18% and 45.71% in average, respectively). This study provides novel insights on lifespan extension in model organisms, and highlights the importance of databases with high quality content curated by researchers from multiple resources, in aging research.
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Proteínas de Caenorhabditis elegans , Longevidad , Envejecimiento , Animales , Caenorhabditis elegans , Drosophila melanogaster , RatonesRESUMEN
The loss of DYNLL1 contributes to chemoresistance in ovarian cancer. DYNLL1 binds to MRE11, a component of MRN complex (MRE11-RAD50-NBS1), and limits its function in homologous recombination (HR) repair in BRCA1-mutant cells. Decreased activity of MRE11 results in less HR-repair events and thus leads to higher sensitivity against DNA-damaging agents such as cisplatin. Therefore, a better understanding of the cellular changes in DYNLL1-MRN axis in ovarian cancer is needed. Here, we showed that DYNLL1 overexpression leads to decreased chemoresistance even in BRCA-proficient ovarian cancer cells. ATMIN, a transcriptional activator of DYNLL1, showed decreased expression; however, two components of MRN complex, MRE11 and NBS1 (NBN), showed increased expression in high grade compared to low grade serous ovarian cancer. We found that the components of MRN complex (MRE11-RAD50-NBS1) have higher protein levels in sites of omental metastasis and serous tubal intraepithelial carcinoma (STIC) compared to surrounding non-malignant stromal cells in patients with high grade serous ovarian cancer. We showed that the percentage of copy number variation (CNV) events in genes encoding ATMIN, DYNLL1, MRE11 and NBN are the highest in ovarian cancer among other cancer types. ATMIN and DYNLL1 genes are mostly characterized by copy number losses; however, CNV events in MRN complex components are mostly copy number gains. This study highlights the importance of ATMIN-DYNLL1-MRN axis in the development, progression and therapy response of ovarian cancer. MRN levels in ovarian cancer that differ from adjacent, non-malignant tissues may represent actionable therapeutic vulnerabilities.