RESUMEN
Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element-derived double-stranded RNAs, thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.
Asunto(s)
Inestabilidad Genómica , N-Metiltransferasa de Histona-Lisina , Hipoxia , Humanos , Genes Supresores de Tumor , N-Metiltransferasa de Histona-Lisina/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Invasividad Neoplásica , Progresión de la Enfermedad , Factores de RiesgoRESUMEN
Biological control agents including microbes and their products have been studied as sustainable crop protection strategies. Although aquatic microalgae have been recently introduced as a biological control agent, the underlying molecular mechanisms are largely unknown. The aim of the present study was to investigate the molecular mechanisms underlying biological control by microalga Chlorella fusca. Foliar application of C. fusca elicits induced resistance in Arabidopsis thaliana against Pseudomonas syringae pv. tomato DC3000 that activates plant immunity rather than direct antagonism. To understand the basis of C. fusca-triggered induced resistance at the transcriptional level, we conducted RNA sequencing (RNA-seq) analysis. RNA-seq data showed that, upon pathogen inoculation, C. fusca treatment primed the expression of cysteine-rich receptor-like kinases, WRKY transcription factor genes, and salicylic acid and jasmonic acid signalling-related genes. Intriguingly, the application of C. fusca primed pathogen-associated molecular pattern -triggered immunity, characterized by reactive oxygen species burst and callose deposition, upon flagellin 22 treatment. The attempts to find C. fusca determinants allowed us to identify d-lactic acid secreted in the supernatant of C. fusca as a defence priming agent. This is the first report of the mechanism of innate immune activation by aquatic microalga Chlorella in higher plants.
Asunto(s)
Arabidopsis/inmunología , Chlorella/inmunología , Ácido Láctico/metabolismo , Enfermedades de las Plantas/inmunología , Reguladores del Crecimiento de las Plantas/metabolismo , Pseudomonas syringae/inmunología , Arabidopsis/genética , Arabidopsis/microbiología , Chlorella/genética , Chlorella/microbiología , Ciclopentanos/metabolismo , Flagelina/metabolismo , Glucanos/metabolismo , Oxilipinas/metabolismo , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta , Especies Reactivas de Oxígeno/metabolismo , Ácido Salicílico/metabolismoRESUMEN
PURPOSE: The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients. METHODS: Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI). RESULTS: Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival. CONCLUSIONS: We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.
Asunto(s)
Antígeno B7-H1 , Neoplasias de la Mama Triple Negativas , Genómica , Humanos , Inmunohistoquímica , PronósticoRESUMEN
BACKGROUND: Because of the heterogeneity of metastatic colorectal cancer (mCRC), a genome-wide analysis was performed to characterize the tumor immune microenvironment (TIME). METHODS: RNA-seq analysis of 62 primary CRCs without and 63 with systemic metastasis (SM- and SM+ groups) was conducted, and the data were used in a training set after adjustment by propensity score matching. Samples were further subdivided into those with hepatic metastasis (CHM subgroup), pulmonary metastasis (CPM subgroup), or concurrent CHM and CPM (concurrent group). Validation was done by quantitative reverse-transcription polymerase chain reaction using another 40 primary CRC samples. RESULTS: Compared with the CHM or CPM subgroups, the concurrent group showed upregulated in inflammatory or immune processes, cytokine secretion, and myeloid leukocyte migration. Nine candidate genes were selected: SM-specific IDO1, JAM3, and PDE2A; CHM- or CPM-specific BIRC7; CPM-specific HISI1H2BK, and both SM-specific and CHM- or CPM-specific EPHB6, LPL, THBD, and PPBP. In a validation set of primary CRCs, JAM3 and IDO1 (p = 0.044 and p = 0.036, respectively) were confirmed to show significant upregulation and downregulation, respectively, in the SM+ group, whereas HIST1H2BK (p = 0.017) was significantly upregulated in the CPM subgroup. CONCLUSIONS: Our findings indicate that a host-suppressive TIME is established in the primary tumor of mCRC and identify immune-related site-specific markers of mCRC.
Asunto(s)
Adenocarcinoma/patología , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Microambiente Tumoral/genética , Estudios de Casos y Controles , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Regulación hacia Abajo , Femenino , Estudio de Asociación del Genoma Completo , Histonas/genética , Histonas/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Regulación hacia ArribaRESUMEN
Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Administración Intravesical , Vacuna BCG/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Transcriptoma , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim to identify a prognostic and predictive signature of diffuse-type GC heterogeneity. METHODS: We analyzed RNA-seq-based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse-type GCs. The predictive value of the signature was verified using other diffuse-type GC samples in three independent cohorts (n = 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes. RESULTS: Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53-2.77, P = 1.76 × 10-6). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity. CONCLUSIONS: We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Intestinales/clasificación , Neoplasias Gástricas/clasificación , Transcriptoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Movimiento Celular , Proliferación Celular , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Recent investigations reported that some subtypes from the Lund or The Cancer Genome Atlas (TCGA) classifications were most responsive to PD-L1 inhibitor treatment. However, the association between previously reported subtypes and immune checkpoint inhibitor (ICI) therapy responsiveness has been insufficiently explored. Despite these contributions, the ability to predict the clinical applicability of immune checkpoint inhibitor therapy in patients remains a major challenge. Here, we aimed to re-classify distinct subtypes focusing on ICI responsiveness using gene expression profiling in the IMvigor 210 cohort (n = 298). Based on the hierarchical clustering analysis, we divided advanced urothelial cancer patients into three subgroups. To confirm a prognostic impact, we performed survival analysis and estimated the prognostic value in the IMvigor 210 and TCGA cohort. The activation of CD8+ T effector cells was common for patients of classes 2 and 3 in the TCGA and IMvigor 210 cohort. Survival analysis showed that patients of class 3 in the TCGA cohort had a poor prognosis, while patients of class 3 showed considerably prolonged survival in the IMvigor 210 cohort. One of the distinct characteristics of patients in class 3 is the inactivation of the TGFß and YAP/TAZ pathways and activation of the cell cycle and DNA replication and DNA damage (DDR). Based on our identified transcriptional patterns and the clinical outcomes of advanced urothelial cancer patients, we constructed a schematic summary. When comparing clinical and transcriptome data, patients with downregulation of the TGFß and YAP/TAZ pathways and upregulation of the cell cycle and DDR may be more responsive to ICI therapy.
Asunto(s)
Inmunoterapia/métodos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias Urológicas/genética , Neoplasias Urológicas/terapia , Antígenos CD8/metabolismo , Ciclo Celular/genética , Ciclo Celular/fisiología , Análisis por Conglomerados , Daño del ADN/genética , Daño del ADN/fisiología , Replicación del ADN/genética , Replicación del ADN/fisiología , Humanos , Pronóstico , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias Urológicas/inmunologíaRESUMEN
DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our previous study has identified E2F1 as a key gene in bladder cancer progression. In this study, DNA repair genes related to E2F1 were analyzed, and RAD54L involved in HRR was identified. In gene expression analysis of bladder cancer patients, the survival of patients with high RAD54L expression was shorter with cancer progression than in patients with low RAD54L expression. This study also revealed that E2F1 directly binds to the promoter region of RAD54L and regulates the transcription of RAD54L related to the HRR pathway. This study also confirmed that DNA breaks are repaired by RAD54L induced by E2F1 in bladder cancer cells treated with MMC. In summary, RAD54L was identified as a new target directly regulated by E2F1. Our results suggest that, E2F1 and RAD54L could be used as diagnostic markers for bladder cancer progression and represent potential therapeutic targets.
Asunto(s)
ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Factor de Transcripción E2F1/metabolismo , Reparación del ADN por Recombinación , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Secuencia de Bases , Línea Celular Tumoral , Roturas del ADN de Doble Cadena/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Mitomicina/farmacología , Pronóstico , Reparación del ADN por Recombinación/genética , Activación Transcripcional/genéticaRESUMEN
BACKGROUND: Gene-set analysis (GSA) has been commonly used to identify significantly altered pathways or functions from omics data. However, GSA often yields a long list of gene-sets, necessitating efficient post-processing for improved interpretation. Existing methods cluster the gene-sets based on the extent of their overlap to summarize the GSA results without considering interactions between gene-sets. RESULTS: Here, we presented a novel network-weighted gene-set clustering that incorporates both the gene-set overlap and protein-protein interaction (PPI) networks. Three examples were demonstrated for microarray gene expression, GWAS summary, and RNA-sequencing data to which different GSA methods were applied. These examples as well as a global analysis show that the proposed method increases PPI densities and functional relevance of the resulting clusters. Additionally, distinct properties of gene-set distance measures were compared. The methods are implemented as an R/Shiny package GScluster that provides gene-set clustering and diverse functions for visualization of gene-sets and PPI networks. CONCLUSIONS: Network-weighted gene-set clustering provides functionally more relevant gene-set clusters and related network analysis.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Mapeo de Interacción de Proteínas/métodos , Programas Informáticos , Algoritmos , Animales , Diabetes Mellitus Tipo 2/genética , Regulación de la Expresión Génica , Humanos , Neoplasias/genéticaRESUMEN
Precise cell cycle regulation is critical to prevent aberrant cell proliferation and cancer progression. Cks1 was reported to be an essential accessory factor for SCFSkp2, the ubiquitin ligase that targets p27Kip1 for proteasomal degradation; these actions drive mammalian cell transition from G1 to S phase. In this study, we investigated the role played by Cks1 in the growth and progression of human hepatocellular carcinoma (HCC) cells. Silencing Cks1 expression abrogated osteopontin (OPN) expression in a p27Kip1-dependent manner in Huh7 HCC cells. OPN increased the proliferation, migration and invasion of Huh7 cells. Pharmacological inhibitor studies demonstrated that ERK1/2 signaling is responsible mainly for Cks1-mediated OPN expression. Cks1 appears to regulate ERK1/2 signaling through the expression of dual-specificity phosphatase 16 (DUSP16) because both Cks1 knockdown, which leads to DUSP16 upregulation, and DUSP16 overexpression decreased ERK1/2 phosphorylation and the resulting OPN expression. The same is true for the Cks1-mediated increases in p27Kip1, suggesting that Cks1 regulates OPN expression through activating ERK1/2 signaling either by suppressing DUSP16 expression or by a p27Kip1-dependent mechanism. Cks1 and OPN expression levels were significantly higher, but DUSP16 expression levels were significantly lower in HCC tissues than in normal liver tissues. Both Cks1 and OPN expression were negatively correlated with DUSP16 expression, whereas Cks1 expression was positively correlated with OPN expression. Moreover, combined panels for the expression levels of Cks1, DUSP16 and OPN showed significant prognostic power for the risk assessment of HCC patient overall survival. In conclusion, our data propose a novel function for Cks1 as a tumor promoter through the expression of the strongly oncogenic protein OPN in HCC.
Asunto(s)
Quinasas CDC2-CDC28/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Osteopontina/biosíntesis , Osteopontina/genética , Línea Celular Tumoral , Proliferación Celular , Humanos , Neoplasias Hepáticas/diagnóstico , Osteopontina/metabolismoRESUMEN
Background and Aims: Sound is omnipresent in nature. Recent evidence supports the notion that naturally occurring and artificially generated sound waves induce inter- and intracellular changes in plants. These changes, in turn, lead to diverse physiological changes, such as enhanced biotic and abiotic stress responses, in both crops and model plants. Methods: We previously observed delayed ripening in tomato fruits exposed to 1 kHz sound vibrations for 6 h. Here, we evaluated the molecular mechanism underlying this delaying fruit ripening by performing RNA-sequencing analysis of tomato fruits at 6 h, 2 d, 5 d and 7 d after 1 kHz sound vibration treatment. Key Results: Bioinformatic analysis of differentially expressed genes and non-coding small RNAs revealed that some of these genes are involved in plant hormone and cell wall modification processes. Ethylene and cytokinin biosynthesis and signalling-related genes were downregulated by sound vibration treatment, whereas genes involved in flavonoid, phenylpropanoid and glucan biosynthesis were upregulated. Furthermore, we identified two sound-specific microRNAs and validated the expression of the pre-microRNAs and the mRNAs of their target genes. Conclusions: Our results indicate that sound vibration helps to delay fruit ripening through the sophisticated regulation of coding and non-coding RNAs and transcription factor genes.
Asunto(s)
Frutas/efectos de la radiación , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Solanum lycopersicum/efectos de la radiación , Sonido , Vibración , Frutas/crecimiento & desarrollo , Perfilación de la Expresión Génica , Solanum lycopersicum/genética , Solanum lycopersicum/crecimiento & desarrollo , Solanum lycopersicum/metabolismo , ARN de Planta/genética , ARN de Planta/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , Factores de TiempoRESUMEN
SUMMARY: Because cancer has heterogeneous clinical behaviors due to the progressive accumulation of multiple genetic and epigenetic alterations, the identification of robust molecular signatures for predicting cancer outcome is profoundly important. Here, we introduce the APPEX Web-based analysis platform as a versatile tool for identifying prognostic molecular signatures that predict cancer diversity. We incorporated most of statistical methods for survival analysis and implemented seven survival analysis workflows, including CoxSingle, CoxMulti, IntransSingle, IntransMulti, SuperPC, TimeRoc and multivariate. A total of 236 publicly available datasets were collected, processed and stored to support easy independent validation of prognostic signatures. Two case studies including disease recurrence and bladder cancer progression were described using different combinations of the seven workflows. AVAILABILITY AND IMPLEMENTATION: APPEX is freely available at http://www.appex.kr. CONTACT: kimsy@kribb.re.kr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias/genética , Neoplasias/mortalidad , Programas Informáticos , Progresión de la Enfermedad , Genómica , Humanos , Internet , Recurrencia Local de Neoplasia , Pronóstico , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
Despite extensive knowledge of antibiotic-targeted bacterial cell death, deeper understanding of antibiotic tolerance mechanisms is necessary to combat multi-drug resistance in the global healthcare settings. Regulatory RNAs in bacteria control important cellular processes such as cell division, cellular respiration, metabolism, and virulence. Here, we investigated how exposing Escherichia coli to the moderately effective first-generation antibiotic cephalothin alters transcriptional and post-transcriptional dynamics. Bacteria switched from active aerobic respiration to anaerobic adaptation via an FnrS and Tp2 small RNA-mediated post-transcriptional regulatory circuit. From the early hours of antibiotic exposure, FnrS was involved in regulating reactive oxygen species levels, and delayed oxygen consumption in bacteria. We demonstrated that bacteria strive to maintain cellular homeostasis via sRNA-mediated sudden respiratory changes upon sublethal antibiotic exposure.
Asunto(s)
Antibacterianos , ARN , Antibacterianos/farmacología , Anaerobiosis , Respiración de la Célula , Bacterias , Respiración , Regulación Bacteriana de la Expresión GénicaRESUMEN
Soybean is an important agricultural crop known for its high protein and oil content, contributing to essential nutritional and health benefits for humans. Domesticated in China over 5,000 years ago, soybean has since adapted to diverse environments and spread worldwide. This study aimed to investigate the genomic characteristics and population structures of 2,317 publicly available soybean whole-genome sequences from diverse geographical regions, including China, Korea, Japan, Europe, North America, and South America. We used large-scale whole-genome sequencing data to perform high-resolution analyses to reveal the genetic characteristics of soybean accessions. Soybean accessions from China and Korea exhibited landrace characteristics, indicating higher genetic diversity and adaptation to local environments. On the other hand, soybean accessions from Japan, the European Union, and South America were found to have low genetic diversity due to artificial selection and breeding for agronomic traits. We also identified key variants and genes associated with the ability to adapt to different environments. In Korean soybean accessions, we observed strong selection signals for isoflavone synthesis, an adaptive trait critical for improving soybean adaptability, survival, and reproductive success by mitigating environmental stress. Identifying specific genomic regions showing unique patterns of selective sweeps for genes such as HIDH, CYP73A11, IFS1, and CYP81E11 associated with isoflavone synthesis provided valuable insights into potential adaptation mechanisms. Our research has significantly improved our understanding of soybean diversity at the genetic level. We have identified key genetic variants and genes influencing adaptability, laying the foundation for future advances in genomics-based breeding programs and crop improvement efforts.
Asunto(s)
Variación Genética , Genoma de Planta , Glycine max , Selección Genética , Secuenciación Completa del Genoma , Glycine max/genética , República de Corea , Genómica/métodos , Polimorfismo de Nucleótido SimpleRESUMEN
Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to c-FLIP (an inhibitor of caspase-8)-depletion-induced apoptosis. Furthermore, in vivo studies demonstrated that c-FLIP knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival. Our in vitro and in vivo analyses also demonstrated that LuAC-BrM is more sensitive to c-FLIP-depletion due to ER stress-induced activation of the c-JUN and subsequent induction of stress genes including ATF4 and DDIT3. Finally, we found that c-JUN not only sensitized LuAC-BrM to c-FLIP-depletion-induced cell death but also promoted brain metastasis in vivo, providing strong evidence for c-JUN's function as a double-edged sword in LuAC-BrM. Collectively, our findings not only reveal a novel link between c-JUN, brain metastasis, and c-FLIP addiction in LuAC-BrM but also present an opportunity for potential therapeutic intervention.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Pulmonares/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Proteína Reguladora de Apoptosis Similar a CASP8 y FADDRESUMEN
Mortalin (encoded by HSPA9) is a mitochondrial chaperone often overexpressed in cancer through as-yet-unknown mechanisms. By searching different RNA-sequencing datasets, we found that ESRRA is a transcription factor highly correlated with HSPA9 in thyroid cancer, especially in follicular, but not C cell-originated, tumors. Consistent with this correlation, ESRRA depletion decreased mortalin expression only in follicular thyroid tumor cells. Further, ESRRA expression and activity were relatively high in thyroid tumors with oncocytic characteristics, wherein ESRRA and mortalin exhibited relatively high functional overlap. Mechanistically, ESRRA directly regulated HSPA9 transcription through a novel ESRRA-responsive element located upstream of the HSPA9 promoter. Physiologically, ESRRA depletion suppressed thyroid tumor cell survival via caspase-dependent apoptosis, which ectopic mortalin expression substantially abrogated. ESRRA depletion also effectively suppressed tumor growth and mortalin expression in the xenografts of oncocytic or ESRRA-overexpressing human thyroid tumor cells in mice. Notably, our Bioinformatics analyses of patient data revealed two ESRRA target gene clusters that contrast oncocytic-like and anaplastic features of follicular thyroid tumors. These findings suggest that ESRRA is a tumor-specific regulator of mortalin expression, the ESRRA-mortalin axis has higher significance in tumors with oncocytic characteristics, and ESRRA target gene networks can refine molecular classification of thyroid cancer.
Asunto(s)
Supervivencia Celular , Receptor Relacionado con Estrógeno ERRalfa , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Proteínas HSP70 de Choque Térmico , Receptores de Estrógenos , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Animales , Ratones , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Apoptosis/genética , Regiones Promotoras Genéticas/genética , Proteínas MitocondrialesRESUMEN
Peritoneal metastases (PM) in colorectal cancer (CRC) is associated with a dismal prognosis. Identifying and exploiting new biomarkers, signatures, and molecular targets for personalised interventions in the treatment of PM in CRC is imperative. We conducted transcriptomic profiling using RNA-seq data generated from the primary tissues of 19 CRC patients with PM. Using our dataset established in a previous study, we identified 1422 differentially expressed genes compared to non-metastatic CRC. The profiling demonstrated no differential expression in liver and lung metastatic CRC. We selected 12 genes based on stringent criteria and evaluated their expression patterns in a validation cohort of 32 PM patients and 84 without PM using real-time reverse transcription-polymerase chain reaction. We selected cartilage intermediate layer protein 2 (CILP2) because of high mRNA expression in PM patients in our validation cohort and its association with a poor prognosis in The Cancer Genome Atlas. Kaplan-Meier survival analysis in our validation cohort demonstrated that CRC patients with high CILP2 expression had significantly poor survival outcomes. Knockdown of CILP2 significantly reduced the proliferation, colony-forming ability, invasiveness, and migratory capacity and downregulated the expression of molecules related to epithelial-mesenchymal transition in HCT116 cells. In an in vivo peritoneal dissemination mouse knockdown of CILP2 also inhibited CRC growth. Therefore, CILP2 is a promising biomarker for the prediction and treatment of PM in CRC.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Neoplasias Peritoneales , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Animales , Ratones , Masculino , Femenino , Pronóstico , Transición Epitelial-Mesenquimal/genética , Proliferación Celular , Células HCT116 , Perfilación de la Expresión Génica , Persona de Mediana Edad , Movimiento Celular , AncianoRESUMEN
Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I-II), and healthy controls (n = 10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T-cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T-cell-related pathways, such as T-cell receptor signaling pathway and T-cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor-infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer.
RESUMEN
The SUVmax is a measure of FDG uptake and is related with tumor aggressiveness in thyroid cancer, however, its association with molecular pathways is unclear. Here, we investigated the relationship between SUVmax and gene expression profiles in 80 papillary thyroid cancer (PTC) patients. We conducted an analysis of DEGs and enriched pathways in relation to SUVmax and tumor size. SUVmax showed a positive correlation with tumor size and correlated with glucose metabolic process. The genes that indicate thyroid differentiation, such as SLC5A5 and TPO, were negatively correlated with SUVmax. Unsupervised analysis revealed that SUVmax positively correlated with DNA replication(r = 0.29, p = 0.009), pyrimidine metabolism(r = 0.50, p < 0.0001) and purine metabolism (r = 0.42, p = 0.0001). Based on subgroups analysis, we identified that PSG5, TFF3, SOX2, SL5A5, SLC5A7, HOXD10, FER1L6, and IFNA1 genes were found to be significantly associated with tumor aggressiveness. Both high SUVmax PTMC and macro-PTC are enriched in pathways of DNA replication and cell cycle, however, gene sets for purine metabolic pathways are enriched only in high SUVmax macro-PTC but not in high SUVmax PTMC. Our findings demonstrate the molecular characteristics of high SUVmax tumor and metabolism involved in tumor growth in differentiated thyroid cancer.