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Menarche, the first menstrual period marking the onset of female reproduction, is a milestone of female puberty. The timing of menarche determines the timing of later phases of pubertal maturation in girls and has major implications for health later in life, including behavioral and psychosocial disorders during adolescence and fertility problems and increased risk for certain diseases in adulthood. Over the last few decades, a continuous decline in age at menarche has been noted, with environmental factors contributing to this change in the timing of menarche. However, a genetic component of age at menarche and pubertal onset has been strongly suggested by studies in families and twins wherein up to approximately 80% of the variance in puberty onset can be explained by heritability. Gene association studies have revealed several genetic loci involved in age at menarche, among which LIN28B has emerged as a key regulator of female growth and puberty. LIN28B, a human homolog of Lin28 of C. elegans, is a known RNA-binding protein that regulates let-7 microRNA biogenesis. Genome-wide association studies have identified the association of polymorphisms in the LIN28B gene with age at menarche in several population cohorts worldwide. In this paper, we review the genetic factors contributing to age of menarche, with particular focus on the identified polymorphisms in LIN28B gene.
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SUMOylation plays a crucial role in numerous cellular biological and pathophysiological processes associated with human disease; however, the mechanisms regulating the genes involved in SUMOylation remain unclear. In the present study, E2F transcription factor 4 (E2F4) was identified as an E2F member related to hepatocellular carcinoma (HCC) progression by public database analysis. It was found that E2F4 promoted the proliferation and invasiveness of HCC cells via SUMOylation using Soft agar and Transwell migration assays. Mechanistically, it was demonstrated that E2F4 upregulated the transcript and protein expression levels of baculoviral IAP repeat containing 5, cell division cycle associated 8 and DNA topoisomerase II α using western blotting. Furthermore, the interaction between E2F4 with lin9 DREAM multivulva class B core complex component (LIN9) was explored by coimmunoprecipitation, immunofluorescence colocalization and bimolecular fluorescence complementation assays. Moreover, it was demonstrated that E2F4 promoted the progression of HCC cells via LIN9. Rescue experiments revealed that LIN9 facilitated the SUMOylation and proliferation of HCC cells, which was prevented by knocking down E2F4 expression. In conclusion, the findings of the present study indicated that E2F4 plays a major role in the proliferation of HCC cells and may be a potential therapeutic target in the future.
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Carcinoma Hepatocelular , Proliferación Celular , Progresión de la Enfermedad , Factor de Transcripción E2F4 , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Sumoilación , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Factor de Transcripción E2F4/metabolismo , Factor de Transcripción E2F4/genética , Línea Celular Tumoral , Movimiento CelularRESUMEN
OBJECTIVE: LIN28B and insulin-like growth factor-1 receptor (IGF-1R) play important roles in the growth and metastasis of colorectal cancer (CRC). The relationship between LIN28B and IGF-1R and their co-expression role in CRC is unknown. This study aims to assess whether the combined detection of LIN28B and IGF-1R is a better predictor of prognosis in CRC than either marker alone. METHODS: We used immunohistochemistry to detect LIN28B and IGF-1R protein. The correlation between LIN28B and IGF-1R expression in CRC was determined by the Spearman correlation analysis. The association between LIN28B/IGF-1R expression and clinicopathological features was analyzed, and overall survivals were also performed. RESULTS: The expression of LIN28B and IGF-1R in CRC tissues were significantly higher than that in non-cancerous tissues (P<0.001 and P<0.001, respectively). LIN28B over-expression positively correlated with IGF-1R over-expression (r=0.283, P=0.007). The increased expression of LIN28B and IGF-1R were both significantly correlated with TNM stage, lymph node metastasis and distant metastasis (all P<0.05). IGF-1R, not LIN28B, was significantly associated with vascular invasion (P=0.007). Overall survival appears to be lower in patients with high LIN28B expression or/and high IGF-1R expression than those with low LIN28B expression or/and low IGF-1R expression. In addition, the predictive sensitivity of LIN28B combined with IGF-1R was stronger than that of either one alone. CONCLUSIONS: The combined over-expression of LIN28B and IGF-1R in patients with colorectal cancer may provide a more powerful predictor for CRC prognosis.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Proteínas de Unión al ARN , Receptor IGF Tipo 1 , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Receptor IGF Tipo 1/metabolismo , Masculino , Femenino , Proteínas de Unión al ARN/metabolismo , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismo , AdultoRESUMEN
Uranium fission fragments, as well as the products of 3He(n,p)3H and 10B(n,α)7Li nuclear reactions were utilized in the nuclear reactor for gas ionization and excitation. However, the 6Li(n,α)3H nuclear reaction was less examined. The use of lithium-6 as a surface source of excitation of the gas medium, due to the long path length of tritium nuclei in the gas, allows to excite large volumes of gas as opposed to using 235U or 10B. While investigating the luminescence of noble gases in the core of the IVG.1M research reactor, we noted an appearance of alkali metal lines and a sharp increase in the intensity of these lines at temperatures above 570 K. It was determined that the population of levels of lithium atoms has practically no effect on the population of the 2p-levels of atoms of noble gases. The selectivity of p- and s-levels deactivation by lithium atoms implies the possibility of creating inversion of population at 2p-1s transitions of noble gas atoms. Successful experiments to study the luminescence of gases upon excitation by 6Li(n,α)3H nuclear reaction products allow us to proceed to experiments to achieve the laser action threshold and study the lasing characteristics of gas mixtures at the IGR pulsed nuclear reactor with thermal neutron flux density up to 7â1016 n/cm2s. For this purpose, an experimental device designs were proposed to perform experiments on the IGR reactor. A step-by-step procedure of fabrication of a nuclear-excited source for excitation of gas mixtures is provided. The results of reactor experiments aimed at determining the spectral and temporal characteristics of optical radiation during excitation of gas mixtures by 6Li(n,α)3H nuclear reaction products are presented.
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Lin28A and Lin28B are paralogous RNA-binding proteins that play fundamental roles in development and cancer by regulating the microRNA family of tumor suppressor Let-7. Although Lin28A and Lin28B share some functional similarities with Let-7 inhibitors, they also have distinct expression patterns and biological functions. Increasing evidence indicates that Lin28A and Lin28B differentially impact cancer stem cell properties, epithelial-mesenchymal transition, metabolic reprogramming, and other hallmarks of cancer. Therefore, it is important to understand the overexpression of Lin28A and Lin28B paralogs in specific cancer contexts. In this review, we summarize the main similarities and differences between Lin28A and Lin28B, their implications in different cellular processes, and their role in different types of cancer. In addition, we provide evidence of other specific targets of each lin28 paralog, as well as the lncRNAs and miRNAs that promote or inhibit its expression, and how this impacts cancer development and progression.
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Background: LIN9, a gene associated with various cancers, is considered a tumor suppressor. However, the role of LIN9 in lung adenocarcinoma (LUAD) remains unknown. In this study, we aimed to assess the role of LIN9 in the occurrence and prognosis of LUAD. Methods: Using three-tier HTSeq count RNA sequencing data from The Cancer Genome Atlas, we assessed LIN9 expression for the LUAD dataset using the DESeq2 R package and RT-qPCR experiments. Biological functions were assessed using gene set enrichment analysis (clusterProfiler and GOplot). The expression of LIN9 and the infiltration of immune cells were assessed by Single-sample gene set enrichment analysis. We conducted correlation study using clinical characteristics and receiver operating characteristic curve analysis. The predictive value of LIN9 was determined using univariate and multivariate Cox regression as well as Kaplan-Meier analysis. Additionally, functional studies were conducted to validate its role in the progression of LUAD. Results: Expression of LIN9 was significantly elevated in LUAD, primarily influencing cell cycle, division, and signaling pathways. High LIN9 expression correlated positively with the infiltration of Th2 cells and inversely with that of plasmacytoid dendritic cells. Furthermore, LIN9 was associated with older age and advanced clinical stages, posing risks to overall, progression-free, and disease-specific survival. LIN9 served as a good diagnostic marker, particularly in females, patients aged over 65, and those with clinical N1-3 and M1 stages. Elevated LIN9 expression enhanced proliferation, migration, and invasion of LUAD cells. Conclusion: High LIN9 expression potentially contributes to LUAD occurrence through cell cycle regulation and chromosomal modification. It promotes the malignant characteristics of LUAD cells and holds prognostic value for affected patients.
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BACKGROUND: Single-nucleotide polymorphisms in LIN28B, critical regulators of female growth and puberty, have been linked to age at menarche. METHODS: We assessed the association of rs7759938, rs314280, and rs314276 with menarcheal age in girls of Greek descent. We reviewed the records of 248 girls who had their first menstruation before 18 years and who attended the Greek Departments of Pediatric Endocrinology from January 2021 to July 2023. Genotyping was performed by standard DNA-based methods. Association analyses involved both parametric and non-parametric tests. RESULTS: The average age of breast and pubic hair development was 9.95 years, and the age at menarche was 11.55 years. Menarche occurred ≤11 years (mean 10.24 years) in 108 girls (43.5%) and >11 years (mean 12.55 years) in 140 (56.5%). The girls' menarcheal age correlated significantly with that of their mothers (average 12.1 years, p-value < 0.0001, Spearman's r 0.350). The dominant rs7759938(TT) genotype was the most common (55.2%), followed by the dominant rs314276(CC) (53.2%) and dominant rs314280(TT) (14.5%) genotypes. CONCLUSIONS: There was no association between age at menarche and any of the polymorphism genotypes/alleles or between genotypes/alleles and birth weight, gestational week, mode of delivery, and maternal age at menarche. Future large sample studies are warranted to confirm these results.
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Several studies have reported the relationship between LIN28A gene polymorphisms (rs3811463 T > C and rs34787247 G > A) and cancer susceptibility, but the results are inconsistent and need further clarification. The current study aimed to evaluate their relationship and also to explore the relationship between LIN28A gene expression and immune infiltration, tumor stage, survival prognosis, and drug sensitivity in pan-cancer. The meta-analysis and data mining were completed by STATA software and the GSCA platform, respectively. The meta-analysis showed that the rs3811463 polymorphism was not associated with cancer susceptibility, while the rs34787247 polymorphism was associated with cancer susceptibility in the Chinese population [AA vs. GG: Odd Ratio (OR)=1.98, 95% Confidence Interval (CI)=1.35-2.89, PZ<0.001; GA vs. GG: OR = 1.17, 95%CI= 1.01-1.36, PZ=0.04; (AA + GA) vs. GG: OR = 1.24, 95%CI = 1.07-1.43, PZ=0.004; AA vs. (GA + GG): OR = 1.90, 95%CI = 1.30- 2.78, PZ=0.001; A vs. G: OR = 1.27, 95%CI = 1.12-1.44, PZ<0.001]. LIN28A gene expression was associated not only with immune infiltration, pathological stage, and survival prognosis of certain cancers, but also with sensitivity to multiple anticancer drugs, such as cisplatin, pazopanib, olaparib, and selumetinib. In conclusion, the current study suggested that the rs34787247 G > A polymorphism might be used as a cancer risk marker in the Chinese population, and LIN28A might serve as a prognostic marker and therapeutic target for certain cancers.
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BACKGROUND: Lincomycin (LIN) is extensively used for treating diseases in livestock and promoting growth in food animal farming, and it is frequently found in both the environment and in food products. Currently, most of the methods for detecting lincomycin either lack sensitivity and precision or require the use of costly equipment such as mass spectrometers. RESULT: In this study, we developed a reliable high-performance liquid chromatography-ultraviolet detection (HPLC-UVD) method and used it to detect LIN residue in 11 types of matrices (pig liver and muscle; chicken kidney and liver; cow fat, liver and milk; goat muscle, liver and milk; and eggs) for the first time. The tissue homogenates and liquid samples were extracted via liquid-liquid extraction, and subsequently purified and enriched via sorbent and solid phase extraction (SPE). After nitrogen drying, the products were derivatized with p-toluene sulfonyl isocyanic acid (PTSI) (100 µL) for 30 min at room temperature. Finally, the derivatized products were analyzed by HPLC at 227 nm. Under the optimized conditions, the method displayed impressive performance and demonstrated its reliability and practicability, with a limit of detection (LOD) and quantification (LOQ) of LIN in each matrix of 25-40 µg/kg and 40-60 µg/kg, respectively. The recovery ranged from 71.11% to 98.30%. CONCLUSIONS: The results showed that this method had great selectivity, high sensitivity, satisfactory recovery and cost-effectiveness-fulfilling the criteria in drug residue and actual detection requirements-and proved to have broad applicability in the field of detecting LIN in animal-derived foods.
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Lincomicina , Cromatografía Líquida de Alta Presión/métodos , Animales , Lincomicina/análisis , Análisis de los Alimentos/métodos , Leche/química , Porcinos , Pollos , Límite de Detección , Contaminación de Alimentos/análisis , Reproducibilidad de los Resultados , Análisis Costo-Beneficio , Cabras , Bovinos , Huevos/análisis , Residuos de Medicamentos/análisisRESUMEN
BACKGROUND: The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. METHODS: We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. RESULTS: CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. CONCLUSIONS: Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.
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Adenosina , Progresión de la Enfermedad , ARN Circular , Proteínas de Unión al ARN , Tumor de Wilms , Animales , Femenino , Humanos , Masculino , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Línea Celular Tumoral , Citoplasma/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Pronóstico , ARN Circular/genética , ARN Circular/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Tumor de Wilms/metabolismo , Tumor de Wilms/genética , Tumor de Wilms/patologíaRESUMEN
The mutations in Caenorhabditis elegans (C. elegans) that extend lifespan slow down aging by interfering with several signaling pathways, including the insulin/IGF-1 signaling (IIS) pathway, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR). The tumor suppressor pRb (retinoblastoma protein) is believed to be involved in almost all human cancers. Lin-35, the C. elegans orthologue of the tumor suppressor pRb, was included in the study to explore the effects of insulin and IGF-1 because it has been linked to cancer-related pRb function in mammals and exhibits a tumor suppressor effect by inhibiting mTOR or IIS signaling. According to our results, IGF-1 or insulin increased the lifespan of lin-35 worms compared to N2 worms by increasing fertilization efficiency, also causing a significant increase in body size. It was concluded that the expression of daf-2 and rsks-1 decreased after insulin or IGF-1 administration, thus extending the lifespan of C. elegans lin-35 worms through both IIS and mTOR-dependent mechanisms. This suggests that it was mediated by the combined effect of the TOR and IIS pathways. These results, especially obtained in cancer-associated mutant lin-35 worms, will be useful in elucidating the C. elegans cancer model in the future.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Factor I del Crecimiento Similar a la Insulina , Insulina , Longevidad , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Longevidad/efectos de los fármacos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression.
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Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSCs), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few research studies have explored the mechanism by which damaged ACs (DACs) contribute to PSCs activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSCs-suppressor to PSCs-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSCs. MiRNome profiling showed that let-7 family is significantly enriched in IAC-derived exosomes (>30% miRNome), which partially mediates IACs' suppressive impacts on PSCs. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7 levels in AC-derived exosomes, and thus promoting PSCs activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSCs activation in CP, resulting in reduced pancreatic fibrosis. IAC-derived exosomes hold potential as potent weapons against PSCs activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.
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Células Acinares , Exosomas , Fibrosis , Factor 4 Similar a Kruppel , MicroARNs , Células Estrelladas Pancreáticas , Pancreatitis Crónica , Factor 4 Similar a Kruppel/metabolismo , Animales , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/patología , Exosomas/metabolismo , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/genética , Pancreatitis Crónica/patología , MicroARNs/genética , Células Acinares/metabolismo , Células Acinares/patología , Dependovirus/genética , Ratones , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Modelos Animales de Enfermedad , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Masculino , Técnicas de Cocultivo , Páncreas/metabolismo , Páncreas/patología , Terapia Genética/métodosRESUMEN
Bone non-union is a common fracture complication that can severely impact patient outcomes, yet its mechanism is not fully understood. This study used differential analysis and weighted co-expression network analysis (WGCNA) to identify susceptibility modules and hub genes associated with fracture healing. Two datasets, GSE125289 and GSE213891, were downloaded from the GEO website, and differentially expressed miRNAs and genes were analysed and used to construct the WGCNA network. Gene ontology (GO) analysis of the differentially expressed genes showed enrichment in cytokine and inflammatory factor secretion, phagocytosis, and trans-Golgi network regulation pathways. Using bioinformatic site prediction and crossover gene search, miR-29b-3p was identified as a regulator of LIN7A expression that may negatively affect fracture healing. Potential miRNA-mRNA interactions in the bone non-union mechanism were explored, and miRNA-29-3p and LIN7A were identified as biomarkers of skeletal non-union. The expression of miRNA-29b-3p and LIN7A was verified in blood samples from patients with fracture non-union using qRT-PCR and ELISA. Overall, this study identified characteristic modules and key genes associated with fracture non-union and provided insight into its molecular mechanisms. Downregulated miRNA-29b-3p was found to downregulate LIN7A protein expression, which may affect the healing process after fracture in patients with bone non-union. These findings may serve as a prognostic biomarker and potential therapeutic target for bone non-union.
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Biomarcadores , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/sangre , Biomarcadores/sangre , Redes Reguladoras de Genes , Curación de Fractura/genética , Perfilación de la Expresión Génica , Biología Computacional/métodos , Femenino , Masculino , Ontología de Genes , Regulación de la Expresión Génica , Fracturas no Consolidadas/genética , Persona de Mediana EdadRESUMEN
The paper introduces JIAO Lin's clinical experience in treatment of knee osteoarthritis (KOA) by manual mobilization of meridian muscle regions. Professor JIAO Lin believes that the key to the occurrence and development of KOA lies in the disorder of meridian muscle regions (sinews/fascia). In pathology, four stages are divided, i.e. the acute stage, the blockage stage, the contraction stage and the atrophy stage of muscle regions, characterized as multi-layer, multi-dimensional and multi-morphological distribution. In treatment, based on the principle, "taking pain sites as stimulating points", the sites, with reduced pain threshold and distributed along the meridian muscle regions, are regarded as "acupoints" for intervention. Manual mobilization of meridian muscle regions is the dominant approach, combined with routine acupuncture, heat-sensitive moxibustion, cupping and bloodletting corresponding to the features of syndromes and meridian manifestation at different stages. The comprehensive treatment may restore and reconstruct the physiological functions of the meridian muscle regions around knee joints by "nourishing tendons, strengthening bones and benefiting joints".
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Puntos de Acupuntura , Meridianos , Osteoartritis de la Rodilla , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia por Acupuntura , Osteoartritis de la Rodilla/terapia , Osteoartritis de la Rodilla/fisiopatologíaRESUMEN
The heterochronic genes of the nematode Caenorhabditis elegans control the succession of postembryonic developmental events. The 4 core heterochronic genes lin-14, lin-28, hbl-1, and lin-41 act in a sequence to specify cell fates specific to each of the 4 larval stages. It was previously shown that lin-14 has 2 activities separated in time that promote L1 and L2 developmental events, respectively. Using the auxin-inducible degron system, we find that lin-28 and hbl-1 each have 2 activities that control L2 and L3 events which are also separated in time. Relative to events they control, both lin-28 and hbl-1 appear to act just prior to or concurrently with events of the L2. Relative to each other, lin-28 and hbl-1 appear to act simultaneously. By contrast, the lin-14 activity controlling L2 events precedes those of lin-28 and hbl-1 controlling the same events, suggesting that lin-14's regulation of lin-28 is responsible for the delay. Likewise, the activities of lin-28 and hbl-1 controlling L3 fates act well in advance of those fates, suggesting a similar regulatory gap. lin-41 acts early in the L3 to affect fates of the L4, although it was not possible to determine whether it too has 2 temporally separated activities. We also uncovered a feedback phenomenon that prevents the reactivation of heterochronic gene activity late in development after it has been downregulated. This study places the heterochronic gene activities into a timeline of postembryonic development relative to one another and to the developmental events whose timing they control.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Regulación del Desarrollo de la Expresión Génica , Factores de Transcripción , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Animales , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Larva , Proteínas de Unión al ADN , Proteínas Nucleares , Proteínas RepresorasRESUMEN
The selection of highly productive genotypes with stable performance across environments is a major challenge of plant breeding programs due to genotype-by-environment (GE) interactions. Over the years, different metrics have been proposed that aim at characterizing the superiority and/or stability of genotype performance across environments. However, these metrics are traditionally estimated using phenotypic values only and are not well suited to an unbalanced design in which genotypes are not observed in all environments. The objective of this research was to propose and evaluate new estimators of the following GE metrics: Ecovalence, Environmental Variance, Finlay-Wilkinson regression coefficient, and Lin-Binns superiority measure. Drawing from a multi-environment genomic prediction model, we derived the best linear unbiased prediction for each GE metric. These derivations included both a squared expectation and a variance term. To assess the effectiveness of our new estimators, we conducted simulations that varied in traits and environment parameters. In our results, new estimators consistently outperformed traditional phenotype-based estimators in terms of accuracy. By incorporating a variance term into our new estimators, in addition to the squared expectation term, we were able to improve the precision of our estimates, particularly for Ecovalence in situations where heritability was low and/or sparseness was high. All methods are implemented in a new R-package: GEmetrics. These genomic-based estimators enable estimating GE metrics in unbalanced designs and predicting GE metrics for new genotypes, which should help improve the selection efficiency of high-performance and stable genotypes across environments.
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LIN28A and its homolog LIN28B are highly conserved RNA-binding proteins that play important roles in early embryonic development, somatic cell reprogramming, metabolism and tumorigenesis. LIN28A/B are highly expressed in a variety of malignant tumors such as breast cancer. They play important roles in the initiation, maintenance, and metastasis of tumors and are associated with poor prognosis. Previous studies have shown that the main regulatory mechanisms of LIN28A/B include let-7s dependent ways and let-7s independent ways, such as directly targeting mRNA. In this review, we summarize the function and molecular regulatory mechanisms of LIN28A/B in malignant tumors such as liver cancer, breast cancer and colorectal cancer, in order to provide references for further exploring the function and mechanism of LIN28A/B and their possible roles in clinical applications.
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Neoplasias , Proteínas de Unión al ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Animales , Progresión de la Enfermedad , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genéticaRESUMEN
Background and Objectives: Lung adenocarcinoma is a leading cause of cancer-related mortality despite recent therapeutic advances. Cancer stem cells have gained increasing attention due to their ability to induce cancer cell proliferation through self-renewal and differentiation into multiple cell lineages. OCT4 and LIN28 (and their homologs A and B) have been identified as key regulators of pluripotency in mammalian embryonic (ES) and induced stem (IS) cells, and they are the crucial regulators of cancer progression. However, their exact role in lung adenocarcinoma has not yet been clarified. Materials and Methods: The aim of this study was to explore the role of the pluripotency factors OCT4 and LIN28 in a cohort of surgically resected human lung adenocarcinomas to reveal possible biomarkers for lung adenocarcinoma prognosis and potential therapeutic targets. The expressions of OCT4, LIN28A and LIN28B were analyzed in formalin-fixed, paraffin-embedded tissue samples from 96 patients with lung adenocarcinoma by immunohistochemistry. The results were analyzed with clinicopathologic parameters and were related to the prognosis of patients. Results: Higher OCT4 expression was related to an improved 5-year overall survival (OS) rate (p < 0.001). Nuclear LIN28B expression was lower in stage I and II tumors (p < 0.05) compared to advanced stage tumors. LIN28B cytoplasmic expression was associated with 5-year OS rates not only in univariate (p < 0.005), but also in multivariate analysis (where age, gender, histopathological subtype and stage were used as cofactors, p < 0.01 HR = 2.592). Patients with lower LIN28B expression showed improved 5-year OS rates compared to patients with increased LIN28B expression. Conclusions: Our findings indicate that OCT4 and LIN28B are implicated in lung adenocarcinoma progression and prognosis outcome; thus, they serve as promising prognostic biomarkers and putative therapeutic targets in lung adenocarcinomas.