RESUMEN

Sarcoma is a rare tumor derived from the mesenchymal tissue and mainly found in children and adolescents. The outcome for patients with sarcoma is relatively poor compared with that for many other solid malignant tumors. Sarcomas have a highly heterogeneous pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequently observed in sarcomas. The telomere maintenance mechanism (TMM) has recently been considered as a prognostic factor for patients with sarcomas, and alternative lengthening of telomeres (ALT) positivity has been correlated with poor outcomes in patients with several types of sarcomas. Therefore, telomeres and telomerases may be useful targets for treating sarcomas. This review aims to provide an overview of telomere and telomerase biology in sarcomas.

Asunto(s)

Sarcoma , Telomerasa , Homeostasis del Telómero , Telómero , Humanos , Telomerasa/genética , Telomerasa/metabolismo , Sarcoma/genética , Sarcoma/terapia , Sarcoma/patología , Telómero/genética , Telómero/metabolismo , Homeostasis del Telómero/genética , Pronóstico , Mutación

RESUMEN

Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and was the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while the exons encoding p14ARF remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Células Epiteliales , Próstata , Neoplasias de la Próstata , Telomerasa , Humanos , Masculino , Telomerasa/genética , Telomerasa/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Células Epiteliales/metabolismo , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Exones/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Línea Celular

RESUMEN

Introduction: The prevalence of thyroid nodules and malignancies in the elderly is a growing concern. Thyroid nodules in this population have unique characteristics, requiring careful treatment strategies that balance risks and benefits. Oncocytic carcinoma of the thyroid (OCA) is a rare, aggressive subtype with diagnostic challenges. Methods: This case features an 84-year-old patient who presented with a neck mass and symptoms of asphyxia. Clinical evaluation, imaging studies, and biopsy were conducted to assess the nature of the thyroid lesion. Molecular testing, including genetic analysis, was performed to identify specific mutations associated with OCA and guide treatment decisions. Results: The patient was diagnosed with oncocytic carcinoma of the thyroid. The molecular testing revealed specific genetic mutations indicative of OCA, confirming the diagnosis. The presence of these mutations guided the treatment plan, emphasizing the importance of molecular diagnostics in managing thyroid malignancies, especially in the elderly. Discussion: This case illustrates the complexities of diagnosing and treating thyroid malignancies in the elderly. Biopsy and molecular testing provided diagnostic accuracy and informed treatment. Individualized approaches are essential for better outcomes, especially in aggressive subtypes, balancing the risks and benefits of intervention.

Asunto(s)

Asfixia , Mutación , Regiones Promotoras Genéticas , Telomerasa , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Anciano de 80 o más Años , Telomerasa/genética , Regiones Promotoras Genéticas/genética , Asfixia/genética , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Adenoma Oxifílico/diagnóstico , Femenino , Masculino

RESUMEN

Telomere length (TL) is increasingly recognized as a molecular marker that reflects how reproductive aging affects intergenerational transmissions. Here, we investigated the effects of parental age on offspring survival and the regulation of TL by examining the telomere-elongating activity of telomerase in the Pacific oyster. We assessed the classical hallmarks of aging in parents at three age classes (young, middle-aged, and old) and crossbred them using a split-brood design to examine the consequences of the nine maternal-by-paternal age combinations on their offspring. Reproductive aging leads to increased larval mortality and accelerated telomere shortening in spats, rendering them more susceptible to infection by the Ostreid herpesvirus. Viral exposure stimulates telomerase activity, a response that we identified as adaptive, but weakened by parental aging. While telomerase lengthens a spat's telomere, paradoxically, longer individual TL predicts higher mortality in adults. The telomerase-telomere complex appeared as a conservative biomarker for distinguishing survivors and losers upon exposure to polymicrobial diseases.

Asunto(s)

Envejecimiento , Reproducción , Telomerasa , Animales , Telomerasa/metabolismo , Telomerasa/genética , Telómero/metabolismo , Telómero/genética , Herpesviridae/fisiología , Femenino , Homeostasis del Telómero , Ostreidae/virología

RESUMEN

Living with chronic pain is associated with substantial suffering and high societal costs. Patient reported outcomes (PROM's) and cellular ageing should be considered in pain management. The aim of this study was to explore correlations of PROM's and cellular ageing (telomere length [TL] and telomerase activity [TA]) amongst patients with chronic non-malignant pain. This was an explorative pilot study with cross-sectional design and recruitment was done at two pain rehabilitation facilities in Sweden, with inpatient setting/integrative care and outpatient setting/multimodal care, respectively. Eighty-four patients were enrolled by referral to pain rehabilitation in Sweden. The main outcome measures collected after admission in addition to TL and TA were the following PROMs: Numerical Rating Scale (NRS), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), Five Facets Mindfulness Questionnaire (FFMQ), WHO Quality of Life-Spiritual, Religious and Personal Beliefs (WHOQoL-SRPB) and EuroQol 5 Dimensions (EQ-5D). All the PROM's showed evidence of poor overall health status among the participants. TL correlated negatively with HADS score (r = -.219, p = .047) and positively with WHOQoL-SRPB (r = .224, p = .052). TL did not correlate with any of the pain measures. TA correlated positively with pain spread (r = .222, p = .049). A mediation of the direct effect of spiritual well-being on TL by anxiety and depression could be shown (b = 0.008; p = .045). The correlations between TL and SRPB and anxiety and depression suggest some importance of emotional and SRPB dimensions in pain management, with implications for cellular aging, which may warrant further study. Trial registration: ClinicalTrials.gov Identifier: NCT02459639.

Asunto(s)

Dolor Crónico , Espiritualidad , Telómero , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor Crónico/psicología , Estudios Transversales , Depresión/psicología , Emociones , Medición de Resultados Informados por el Paciente , Proyectos Piloto , Calidad de Vida , Religión , Encuestas y Cuestionarios , Suecia , Telomerasa/metabolismo , Telomerasa/genética , Telómero/genética

RESUMEN

Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, maintaining genomic integrity during the cell cycle. A decrease in average telomere length is associated with with age and with aging-related diseases such as cancer and cardiovascular disease. In this study, we conducted a randomized, double-blind, placebo-controlled trial over six months to compare the effects of the Astragalus-based supplement versus a placebo on telomere length (TL) in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement, and 20 received placebo capsules. All participants completed the study, and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median TL (p = 0.01) and short TL (p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement's intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging.

Asunto(s)

Planta del Astrágalo , Suplementos Dietéticos , Telomerasa , Telómero , Humanos , Método Doble Ciego , Persona de Mediana Edad , Masculino , Femenino , Planta del Astrágalo/química , Telómero/efectos de los fármacos , Telomerasa/metabolismo , Homeostasis del Telómero/efectos de los fármacos , Acortamiento del Telómero/efectos de los fármacos

RESUMEN

An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.

Asunto(s)

Carcinoma Hepatocelular , Proliferación Celular , Canales de Potasio de Conductancia Intermedia Activados por el Calcio , Neoplasias Hepáticas , Sistema de Señalización de MAP Quinasas , Telomerasa , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Telomerasa/metabolismo , Telomerasa/genética , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Masculino , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Desnudos , Apoptosis/efectos de los fármacos , Femenino , Progresión de la Enfermedad , Ratones Endogámicos BALB C , Nanopartículas/química , Persona de Mediana Edad

RESUMEN

Multiple myeloma is a hematological cancer caused by the uncontrolled proliferation of abnormal plasma cells in the bone marrow, leading to excessive immunoglobulin production. Our study aimed to examine the anticancer properties of BRF1A, a cannabinoid (CBD)-enriched product, on 2 myeloma cell lines: U266 and ARH-7. We treated U266 and ARH-77 myeloma cells with varying doses of BRF1A and measured the production of IgE and IgG antibodies using ELISA. Cell viability was assessed using trypan blue and CCK-8 assays. We measured the expression of genes related to the production of IgE and IgG antibodies, IgEH, and IgGH. We determined its effect on the expression of telomerase and its phosphorylated form as an indicator of telomere stabilization. Furthermore, we determined its effect on other cancer-related targets such as NF-ĸB, c-Myc, and TP53 in U266 cells using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. BRF1A reduced myeloma cell IgE and IgG production in a time and dose-dependent manner. It also suppressed the expression of p-IκBα, p-NFκB (p65), and total NFκB protein, as well as XBP1u and XBP1s. It increased the gene and protein expression of telomere and hTERT and significantly increased cancer suppressor TP53 gene and p53 protein expression. Additionally, BRF1A decreased the c-Myc gene and protein expression. Our study has shown that a CBD-enriched product can reduce the growth of myeloma cells by suppressing the critical functions of IgE- and IgG-producing cells. This study could help bridge the gap in understanding how cannabinoid-containing products affect cancer, aging, telomere, and cancer-suppressor gene activity.

Asunto(s)

Cannabinoides , Mieloma Múltiple , Telomerasa , Telómero , Proteína p53 Supresora de Tumor , Humanos , Mieloma Múltiple/tratamiento farmacológico , Línea Celular Tumoral , Telómero/efectos de los fármacos , Telómero/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Cannabinoides/farmacología , Telomerasa/metabolismo , Supervivencia Celular/efectos de los fármacos , FN-kappa B/metabolismo , Inmunoglobulina E , Inmunoglobulina G , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

BACKGROUND: Although the G allele variant of TERT-CLPTM1L rs4975616 has been confirmed to be negatively associated to the risk of lung cancer (LC), some other studies haven't found this negative association. The purpose of this study is to clarify the association of the rs4975616 with the risk of developing LC and the differences of this association among patients with different ethnicities (Caucasians and Asians), different subtypes of LC, and different smoking status. METHODS: Relevant literatures published before July 20, 2023 in PubMed, EMbase, Web of Science, MEDLINE databases were searched through the Internet. Statistical analysis of data was performed in Revman5.3, including drawing forest plots, funnel plots and so on. Sensitivity and publication bias were performed in Stata 14.0. The stability of the results was assessed using Test Sequence Analysis (TSA) software. Registration number: CRD42024568348. RESULTS: The G allele variant of rs4975616 was negatively associated with the risk of LC ([OR] = 0.86, 95%CI [0.84, 0.88]), and that this negative association was present in both Caucasians ([OR] = 0.85, 95%CI [0.83, 0.87]) and Asians ([OR] = 0.91, 95%CI [0.86, 0.95]), and the strength of the negative association was higher in Caucasians than in Asians (subgroup differences: P = 0.02, I2 = 80.3%). Across LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD, LUSC) in both Caucasians and Asians (P<0.05) and the strength of the association with NSCLC (LUAD) was higher in Caucasians than in Asians (Subgroup differences: I2>50%). In Caucasians, rs4975616[G] was negatively associated with the risk of LC in both smokers and non-smokers (P<0.05), and the strength of the association did not differ between smokers and non-smokers (Subgroup differences: P = 0.18, I2 = 45.0%). In Asians, rs4975616[G] was mainly negatively associated with the risk of LC in smokers (P<0.05) but not in non-smokers ([OR] = 0.97, 95%CI [0.78, 1.20]). Comparisons between the two populations showed that the strength of this negative association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: P = 0.04, I2 = 75.3%), whereas the strength of this negative association was the same for Caucasian smokers as for Asian smokers (Subgroup differences: P = 0.42, I2 = 0%). Among the different LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD) incidence in both Asian smokers and Caucasian non-smokers (P<0.05), whereas it was not associated with the risk of NSCLC development in Asian non-smokers (P>0.05). Comparisons between the two populations showed that the strength of the association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: I2>50%). CONCLUSION: The G allele variant of rs4975616 is negatively associated with the risk of LC and NSCLC (LUAD, LUSC). Compared with Asians, Caucasians are more likely to have a higher risk of LC and NSCLC (LUAD) due to the rs4975616 variant. In Caucasians, smoking and other factors like non-smoking contribute to rs4975616 variations leading to LC, and other factors like non-smoking also induce rs4975616 variations leading to NSCLC (LUAD). In Asians, smoking is the major risk factor for the induction of rs4975616 variations leading to LC and NSCLC(LUAD).

Asunto(s)

Pueblo Asiatico , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares , Proteínas de la Membrana , Proteínas de Neoplasias , Polimorfismo de Nucleótido Simple , Telomerasa , Población Blanca , Humanos , Neoplasias Pulmonares/genética , Población Blanca/genética , Telomerasa/genética , Pueblo Asiatico/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Alelos , Factores de Riesgo , Fumar

RESUMEN

Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.

Asunto(s)

Neoplasias Encefálicas , Variaciones en el Número de Copia de ADN , Glioblastoma , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Glioblastoma/genética , Glioblastoma/patología , Masculino , Femenino , Isocitrato Deshidrogenasa/genética , Glioma/genética , Glioma/patología , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Secuenciación del Exoma , Telomerasa/genética , Biomarcadores de Tumor/genética , Clasificación del Tumor , Cadherinas/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Pronóstico , Genómica/métodos , Protocadherinas , Adulto Joven

RESUMEN

BACKGROUND: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD. METHODS: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk. RESULTS: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk. CONCLUSION: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Leucocitos , Análisis de la Aleatorización Mendeliana , Telomerasa , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de los Pequeños Vasos Cerebrales/genética , China , Pueblos del Este de Asia/genética , Predisposición Genética a la Enfermedad , Genotipo , Leucocitos/metabolismo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Telomerasa/genética , Telómero/genética

RESUMEN

OBJECTIVE: To explore whether Resveratrol (RSV) can inhibit the spontaneous senescence of human bone marrow-derived mesenchymal stem cells (MSC). METHODS: MSC were serially cultured to passage 13 and passage 15 to establish model groups exhibiting spontaneous senescence, respectively. MSC at passage 13 and passage 15 were treated with 5 nmol/L RSV for 48 h to establish the RSV-treated groups. SA-ß-Gal staining was used to detect cell senescence. MTT assay was used to detect cell proliferation. RT-PCR method was used to detect senescenceassociated telomerase activity. Western blot was used to detect the senescence-associated protein level of the phosphorylated-mTOR. RESULTS: SA-ß-Gal staining showed that the senescent cells of MSC in RSV-treated group was significantly less than those in the model group (RSV group compared with model group at passage 13, P < 0.05; RSV group compared with model group at passage 15, P < 0.01). The cell proliferation ability of MSC in RSV-treated group was significantly higher than those in model group, at 72 h in passage 13, there was significant difference between RSV-treated group and model group (P < 0.05). RT-PCR results showed that the hTERT mRNA expression of MSC in RSV-treated group was higher than that in model group, which was significantly different between RSV-treated group and model group at passage 13 (P < 0.05). Western blot results showed that the phosphorylated (Ser2448)-mTOR level of MSC in RSV-treated group was lower than that in model group, which was significantly different between RSV-treated group and model group at passage 13 (P < 0.05). CONCLUSION: RSV can inhibit the spontaneous senescence of human MSC by mediating mTOR activity.

Asunto(s)

Células de la Médula Ósea , Proliferación Celular , Senescencia Celular , Células Madre Mesenquimatosas , Resveratrol , Serina-Treonina Quinasas TOR , Telomerasa , Humanos , Resveratrol/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Senescencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células de la Médula Ósea/citología , Células Cultivadas , Telomerasa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Estilbenos/farmacología

RESUMEN

Papillary thyroid carcinoma (PTC), the most common malignancy of follicular cell derivation, is generally associated with good prognosis. Nevertheless, it is important to identify patients with aggressive PTCs and unfavorable outcome. Molecular markers such as BRAFV600E mutation and TERT promoter mutations have been proposed for risk stratification. While TERT promoter mutations have been frequently associated with aggressive PTCs, the association of BRAFV600E mutation with increased recurrence and mortality is less clear and has been controversially discussed. The aim of the present study was to analyze whether differentially expressed genes can predict BRAFV600E mutations as well as TERT promoter mutations in PTCs. RNA sequencing identified a large number of differentially expressed genes between BRAFV600E and BRAFwildtype PTCs. Of those, AHNAK2, DCSTAMP, and FN1 could be confirmed in a larger cohort (n = 91) to be significantly upregulated in BRAFV600E mutant PTCs using quantitative RT-PCR. Moreover, individual PTC expression values of DCSTAMP and FN1 were able to predict the BRAFV600E mutation status with high sensitivity and specificity. The expression of TERT was detected in all PTCs harboring TERT promoter mutations and in 19% of PTCs without TERT promoter mutations. Tumors with both TERT expression and TERT promoter mutations were particularly associated with aggressive clinicopathological features and a shorter recurrence-free survival. Altogether, it will be interesting to explore the biological function of AHNAK2, DCSTAMP, and FN1 in PTC in more detail. The analysis of their expression patterns could allow the characterization of PTC subtypes and thus enabling a more individualized surgical and medical treatment.

Asunto(s)

Mutación , Recurrencia Local de Neoplasia , Telomerasa , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Telomerasa/genética , Femenino , Masculino , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Persona de Mediana Edad , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas de la Membrana/genética , Anciano , Transcriptoma , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas , Proteínas del Citoesqueleto , Fibronectinas

RESUMEN

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Asunto(s)

Proteínas de Ciclo Celular , Fibrosis Pulmonar Idiopática , Proteínas Nucleares , Telomerasa , Acortamiento del Telómero , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Telomerasa/metabolismo , Telomerasa/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Fibroblastos/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Telómero/metabolismo , Telómero/genética , Regulación de la Expresión Génica , Pulmón/metabolismo , Pulmón/patología

RESUMEN

Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.

Asunto(s)

Microbiota , Infecciones por Papillomavirus , Lesiones Precancerosas , Telomerasa , Telómero , Neoplasias del Cuello Uterino , Vagina , Humanos , Femenino , Telomerasa/metabolismo , Telomerasa/genética , Vagina/microbiología , Vagina/virología , Microbiota/genética , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Adulto , Telómero/metabolismo , Telómero/genética , Persona de Mediana Edad , Lesiones Precancerosas/virología , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/microbiología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Homeostasis del Telómero , Papillomaviridae/genética

RESUMEN

Skeletal muscle, which is predominantly constituted by multinucleated muscle fibers, plays a pivotal role in sustaining bodily movements and energy metabolism. Myoblasts, which serve as precursor cells for differentiation and fusion into muscle fibers, are of critical importance in the exploration of the functional genes associated with embryonic muscle development. However, the in vitro proliferation of primary myoblasts is inherently constrained. In this study, we achieved a significant breakthrough by successfully establishing a chicken myoblast cell line through the introduction of the exogenous chicken telomerase reverse transcriptase (chTERT) gene, followed by rigorous G418-mediated pressure screening. This newly developed cell line, which was designated as chTERT-myoblasts, closely resembled primary myoblasts in terms of morphology and exhibited remarkable stability in culture for at least 20 generations of population doublings without undergoing malignant transformation. In addition, we conducted an exhaustive analysis that encompassed cellular proliferation, differentiation, and transfection characteristics. Our findings revealed that the chTERT-myoblasts had the ability to proliferate, differentiate, and transfect after multiple rounds of population doublings. This achievement not only furnished a valuable source of homogeneous avian cell material for investigating embryonic muscle development, but also provided valuable insights and methodologies for establishing primary cell lines.

Asunto(s)

Diferenciación Celular , Proliferación Celular , Pollos , Mioblastos , Telomerasa , Animales , Mioblastos/citología , Mioblastos/metabolismo , Línea Celular , Telomerasa/metabolismo , Telomerasa/genética , Desarrollo de Músculos/genética , Técnicas de Cultivo de Célula/métodos , Transfección , Embrión de Pollo

RESUMEN

Understanding the complex dynamics of telomere biology is important in the strong link between aging and cancer. Telomeres, the protective caps at the end of chromosomes, are central players in this connection. While their gradual shortening due to replication limits tumors expansion by triggering DNA repair mechanisms, it also promotes oncogenic changes within chromosomes, thus sustaining tumorigenesis. The enzyme telomerase, responsible for maintaining telomere length, emerges as a central player in this context. Its expression in cancer cells facilitates the preservation of telomeres, allowing them to circumvent the growth-limiting effects of short telomeres. Interestingly, the influence of telomerase extends beyond telomere maintenance, as evidenced by its involvement in promoting cell growth through alternative pathways. In this context, inflammation accelerates telomere shortening, resulting in telomere dysfunction, while telomere elements also play a role in modulating the inflammatory response. The recognition of this interplay has promoted the development of novel therapeutic approaches centered around telomerase inhibition. This review provides a comprehensive overview of the field, emphasizing recent progress in knowledge and the implications in understanding of cancer biology.

Asunto(s)

Envejecimiento , Inflamación , Neoplasias , Telomerasa , Telómero , Telomerasa/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Envejecimiento/metabolismo , Envejecimiento/genética , Animales , Telómero/metabolismo , Telómero/genética , Homeostasis del Telómero , Acortamiento del Telómero

RESUMEN

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

Asunto(s)

Neoplasias Encefálicas , Islas de CpG , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación de ADN/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Islas de CpG/genética , Niño , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Epigenoma , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Masculino , Telomerasa/genética , Femenino

RESUMEN

Numerous studies have investigated seed aging, with a particular emphasis on the involvement of reactive oxygen species. Reactive oxygen species diffuse into the nucleus and damage telomeres, resulting in loss of genetic integrity. Telomerase reverse transcriptase (TERT) plays an essential role in maintaining plant genomic stability. Genome-wide analyses of TERT genes in alfalfa (Medicago sativa) have not yet been conducted, leaving a gap in our understanding of the mechanisms underlying seed aging associated with TERT genes. In this study, four MsTERT genes were identified in the alfalfa genome. The expression profiles of the four MsTERT genes during seed germination indicated that MS. gene79077 was significantly upregulated by seed aging. Transgenic seeds overexpressing MS. gene79077 in Arabidopsis exhibited enhanced tolerance to seed aging by reducing the levels of H2O2 and increasing telomere length and telomerase activity. Furthermore, transcript profiling of aging-treated Arabidopsis wild-type and overexpressing seeds showed an aging response in genes related to glutathione-dependent detoxification and antioxidant defense pathways. These results revealed that MS. gene79077 conferred Arabidopsis seed-aging tolerance via modulation of antioxidant defense and telomere homeostasis. This study provides a new way to understand stress-responsive MsTERT genes for the potential genetic improvement of seed vigor.

Asunto(s)

Arabidopsis , Regulación de la Expresión Génica de las Plantas , Medicago sativa , Semillas , Telomerasa , Homeostasis del Telómero , Telómero , Arabidopsis/genética , Medicago sativa/genética , Telomerasa/genética , Telomerasa/metabolismo , Semillas/genética , Telómero/genética , Telómero/metabolismo , Plantas Modificadas Genéticamente , Germinación/genética , Peróxido de Hidrógeno/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Antioxidantes/metabolismo , Senescencia de la Planta/genética

RESUMEN

BACKGROUND: Ceranib-2, an acid ceramidase (AC) inhibitor, can inhibit cancer cell proliferation and tumor development. However, poor water solubility and low cellular bioavailability limit its efficacy in cancer treatment. METHODS AND RESULTS: This study aimed to investigate the cell death induced by ceranib-2 and its solid lipid nanoformulation (ceranib-2-SLN) produced by the hot homogenization technique and the synergistic relationship between ceramide and telomerase in vitro and in silico. Furthermore, this study proved the possible mechanism of ceranib-2-induced AC inhibition by in silico studies. The effective cytotoxic concentrations of ceranib-2, telomerase level, and changes in ceramide levels were measured by MTT colorimetric cytotoxicity assay, ELISA, and LC/MS/MS methods, respectively. TEM results showed that ceranib-2-SLN was 13-fold smaller than the size of ceranib-2. Ceranib-2 and ceranib-2-SLN had IC50 concentrations of 31.62 (± 2.1) and 27.69 (± 1.75) µM in A549, and 48.79 (± 1.56) and 67.98 (± 2.33) in Beas-2B cells. These compounds simultaneously increased ceramide levels and decreased telomerase levels in A549 cells. Ceranib-2 increased telomerase levels while decreasing ceramide levels in Beas-2B cells. It was shown how the synergistic impact of ceranib-2-induced ceramide production and ceramide-induced telomerase level reduction on cytotoxicity in A549 cells. CONCLUSIONS: Ceranib-2-SLN was discovered to be more cytotoxic on cancer cells than ceranib-2, suggesting that it could be a promising option for the development of a new anti-cancer agent.

Asunto(s)

Telomerasa , Humanos , Telomerasa/metabolismo , Telomerasa/antagonistas & inhibidores , Línea Celular Tumoral , Células A549 , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Ceramidas/metabolismo , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos